Proposal #: 15-11

2013 FASEB SCIENCE RESEARCH CONFERENCES ADVISORY COMMITTEE MEETING

TOPIC FOR CONSIDERATION TOPIC NAME: HDACs, Sirtuins, and Reversible Lysine Modifications PREVIOUS TITLE: HISTONE DEACETYLASES, SIRTUINS AND REVERSIBLE ACETYLATION IN SIGNALING AND

DISEASE SUBMITTED BY: David A. Sinclair, Harvard Medical School

Ming-Ming Zhou, Icahn School of Medicine at Mt. Sinai, NY YEAR REQUESTED FOR

SCHEDULING: 2015

SITE REQUESTS: 1. Il Ciocco Resort, Barga, Italy

2. Suzhou Conference Center, Shanghai, China 3. Nassau, Bahamas

DATE REQUESTS: 1. August 9-14, 2015

2. August 16-21, 2015 3. August 23-28, 2015

YEAR(S) CONFERENCE

HAS BEEN HELD: 2007, 2009, 2011, 2013

NOTES: To the best of our knowledge, there is not a direct conflict with any other

FASEB SRC or other society or industry meeting.

Section 2: Conference Title & Organizer Information:

Please insert the title of the conference as you would like it to be advertised in future publications. List the organizer(s) complete contact information and attach brief CVs (maximum 3 pages) in NIH format for each. Title of Conference: HDACs, sirtuins, and reversible lysine modifications Organizer & Co-Organizer Information: Organizer 1: David A. Sinclair Title: Professor of Genetics Affiliation: Department of Genetics, Harvard Medical School Full Address: NRB933, 77 Ave Louis Pasteur, Boston, USA 02115 Phone: 617 432 3932; Email: david_sinclair@hms.harvard.edu

Organizer 2: Ming-Ming Zhou Title: Professor and Chair, Structural &

Chemical Biology

Affiliation: Icahn School of Medicine at Mount Sinai, NY

Full Address: 1425 Madison Ave., New York, NY 10029

Phone: 212-659-8652 Email: Ming-ming.zhou@mssm.edu

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Section 3: Program Submission Requirements & Outline:

Please insert program details in day order as requested below. Session titles should be listed with session chairs and affiliations. Indicate the proposed tentative talk titles within each session and list up to at least 4 speakers per session (not including short talks selected from submitted abstracts). Please remember to also include the required “Meet the Expert” session. The FASEB SRC Advisory Committee requires all session chairs to be confirmed before the submission of the application. Be sure to indicate with a "C" if the session chair is confirmed, indicate with a “CS” if the speaker is confirmed, indicate with a "W" which session chairs and speakers are women, indicate with an "M" which session chairs and speakers are of a minority group and indicate with the word “NEW” which session chairs and speakers are new to the program. (Note: The committee defines new speakers as one that has NOT spoken at the last two (2) conferences.) NOTE: Chairs will be given a speaking slot within their session. Day One (Sunday): Afternoon: Conference Registration Evening: FASEB SRC Welcome Reception & Dinner Keynote Speaker (optional): Name: __ Paulo Sassone-Corsi (C) Affiliation: _ UC Irvine, CA, USA ___________________ Tentative Title of Talk:Acetylation links Metabolism, Circadian Clocks and Disease ___ Day Two Session 1 (Monday AM): Title of Session: _ Aging and Age Related Diseases_______ Session Chair & Affiliation: _Lenny Guarente_________ Speaker 1: _ Shin Imai_______________________________ Affiliation: __ Washington University ___________________________ Tentative Title of Talk: _ NAD at the intersection of metabolism, aging and lifespan__ Speaker 2: __ Raul Mostolavsky______________________________ Affiliation: _Harvard Medical School____________________________ Tentative Title of Talk: __Sirtuins and metabolic reprogramming in cancer _ Speaker 3: _Katrin Chua ___(W)____________________________ Affiliation: __Stanford University_ __________________________ Tentative Title of Talk: _The role of SIRT6/7 in control of gene expression in chromatin_ Speaker 4: __ Kathleen Sakamoto ___(W)__ ______________________ Affiliation: __ UCLA Tentative Title of Talk: _Chemoproteomic analysis of HDAC complexes Number of short talks selected from abstracts: _2____

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Poster Session 1 Session 2 (Monday PM): Title of Session: _New Lysine Modifications_

Session Chair & Affiliation: Matthias Mann, Max Planck Institute, Germ. (New) ____ Speaker 1: __ Brad Gibson __(New)____________________________

Affiliation: _ __ Buck Institute, Novato, CA_________ Tentative Title of Talk: __Regulation of gene expression by histone acetylation__ Speaker 2: _ Anthony Sauve (New)________ Affiliation: _Weill-Cornell Medical School, NY _____ Tentative Title of Talk: _Sirtuin enzymology and novel substrates ___ Speaker 3: _ Melanie Ott_(W)_______________________ Affiliation:__Gladstone, UCSF________________ Tentative Title of Talk: _New lysine modifications in gene transcription _____________ Speaker 4: _ Hening Lin____________________ Affiliation: __Cornell University ___________________________ Tentative Title of Talk: _Acyl lysine modifications in immune function___________ Number of short talks selected from abstracts: __2___ Day Three Session 3 (Tuesday AM): Title of Session: _ Protein Acetylation In Metabolism_____________ Session Chair & Affiliation: _Eric Verdin, UCSF, Gladstone_______ Speaker 1: _ Johan Auwerx__(New)___________________________ Affiliation: __ Ecole Polytechnique Fédérale, Switzerland__________________ Tentative Title of Talk: _New insights into acetylation of type 2 diabetes _ Speaker 2: _ John Denu ______________ Affiliation: ___Univ. of Wisconsin __________________________ Tentative Title of Talk: _ Physiological functions of protein acetylation______ Speaker 3: Danica Chen_(New, W)_____________________ Affiliation: _UC Berkeley___________________________ Tentative Title of Talk: _Lysine modification in stem cell functions __ Speaker 4: _Haim Cohen (New)____or Scott Hiebert___________________________ Affiliation: __Bar Ilan University, Israel__/ Vanderbilt University, Nashville, TN_____ Tentative Title of Talk: _SIRT6 suppresses metabolic decline and inflammation Number of short talks selected from abstracts: __2___

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Poster Session 2 Session 4 (Tuesday PM): Title of Session: _ Metabolism and Gene Expression Session Chair & Affiliation: _ Shelley Berger (New, W), U. Penn _ Speaker 1: _Wei Gu____(C)_______ Affiliation: _Herbert Irving Cancer Research Center___________ Tentative Title of Talk: __Regulation of p53 by acetylation__________ Speaker 2: Ronen Marmorstein __(New)_______ Affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy Tentative Title of Talk: _Sirtuins and HDACs in regulating chromatin _ Speaker 3: __ Charles Mobs (New)____________________ Affiliation: __Icahn School of Medicine at Mount Sinai Tentative Title of Talk: __CBP regulates health and lifespan __ Speaker 4: _Saghi Graffair (New, W)_____________________________ Affiliation: _ Icahn School of Medicine at Mount Sinai ________________ Tentative Title of Talk: SIRT1 and hematopoietic stem cells Number of short talks selected from abstracts: __2___ Day Four Session 5 (Wednesday AM): Title of Session: _ Chromatin and Gene Regulation _ Session Chair & Affiliation: __ David Allis (New), Rockefeller University____ Speaker 2: _Jerry Workman or Michael Yaffe (New)_________________________ Affiliation: __ Stowers Institute _/ M.I.T._______________ Tentative Title of Talk: _Histone acetylation as an chromatin insulator _____ Speaker 2: _Robert Roeder (New)_________________________ Affiliation: __ Rockefeller University ________________ Tentative Title of Talk: _Mechanisms of gene transcription in chromatin_________ Speaker 3: _Vera Gorbunova_ (New, CS, W)_____________________________ Affiliation: __ Rochester University, NY___________________________ Tentative Title of Talk: _ Roles for acetylation and PARylation in DNA repair and transcription.___ Speaker 4: __ Martin Walsh (New)___________________________ Affiliation: __ Icahn School of Medicine at Mount Sinai____________________ Tentative Title of Talk: Non-coding RNA in regulation of gene expression _ Number of short talks selected from abstracts: __2___

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Session 6 (Wednesday PM): Title of Session: _ Transcription in Biology and Disease_ Session Chair & Affiliation: __ Stephen Nimer, University of Miami Cancer Center ____ Speaker 1: _Michael Ristow__ (New) or Michael Potente _______ Affiliation: __ University of Jena / Max-Planck-Institute, Germany.______________ Tentative Title of Talk: _Methyl-nicotinamide, a new regulator of acetylation and lifespan Speaker 2: __ Stephanie Dimmeler ___(New, W)___________________________ Affiliation: __Groethe Univ. Frankfurt___________________________ Tentative Title of Talk: _Regulation of cardiovascular regeneration by Sirtuins___ Speaker 3: ___ Saadi Khochbin_________________ Affiliation: __ Institut Albert Bonniot, Grenoble_ Tentative Title of Talk: _Role of acetylation in genome progamming__ Speaker 4: __ Li-Huei Tsai_(W)_____________________________ Affiliation: __M.I.T.___________________________ Tentative Title of Talk: Sirtuins and HDACs cooperate in DNA repair and cognition__ Number of short talks selected from abstracts: __2___ Day Five Session 7 (Thursday AM): Title of Session: _ Advance in Epigenetic Drug Discovery____ Session Chair & Affiliation: __ Victoria Richon, Epizyme_(New, W)__ Speaker 1: _Peter Atadja__(M)________ Affiliation: _Novartis____________________________ Tentative Title of Talk: _Anti-cancer activities of HDAC inhibitors___ Speaker 2: _ Jim Ellis________________________ Affiliation: __ _GSK_______________ Tentative Title of Talk: _Mechanistic and clinical advances in targeting sirtuins Speaker 3: _ _ James Rusche_(New)____________ Affiliation: _ Repligen (JR)___________________________ Tentative Title of Talk: _Histone acetylation as a therapeutic target; or Targeting HDAC3 in Ataxia___ Speaker 4: _Bob Sims______________________________ Affiliation: ___Constellation Pharma ___________________ Tentative Title of Talk: __Reversible acetylation as a drug target ____ Number of short talks selected from abstracts: __2___

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Session 8 (Thursday PM): Title of Session: _Novel Approaches of Studying Lysine Modifications_____ Session Chair & Affiliation: Phillip Cole, Johns Hopkins University Medical School____ Speaker 1: _ Chuna Choudhary __(CS)_____________________________ Affiliation: __ Univ. of Copenhagen__________________ Tentative Title of Talk: _Using quantitative proteomics identify acetylated proteins_ Speaker 2: __ Ying-Ming Zhao ______________________________ Affiliation: _ University of Chicago_ Tentative Title of Talk: _Assessing the acylome by mass spectrometry Speaker 3: __ Tso-Pang Yao ______________________________ Affiliation: ___Duke__________________________ Tentative Title of Talk: __Modulation of protein stability by PTMs_________ Speaker 4: _Reuben Shaw___(New)____________________________ Affiliation: _ The Salk Institute for Biological Studies, La Jolla, CA_____ Tentative Title of Talk: _ Class IIa histone deacetylases are hormone-activated regulators of mammalian glucose homeostasis_

Number of short talks selected from abstracts: __2___ Day Six Session 9 (Friday AM - Optional): End of Conference

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Section 4: Content Assessment Indicate the number of session chairs that have confirmed their participation: 2

Indicated the number of women included with the entire program: 8

Indicate the number of session chairs/speakers of a minority group: 1

Indicate the number of “new” speakers to the conference: 16

Indicate the number of speakers that have confirmed their participation: 5

Indicated the number of talks set aside for junior level investigators to present: 20

Indicated the number of poster sessions that will be organized: 2

Please provide a brief description of the how the poster sessions will be organized: We will request that the posters be in position throughout the length of the meeting to allow the participants as much time as possible to peruse the information. The two poster sessions will be segregated such that the presenters for the even numbered posters will be present during the first session and the odd numbered the second. This will allow the presenters to have the opportunity to interact with the other presenters. In addition to the formal poster sessions, a committee composed of the organizers and the session chairs will select two presentations from posters in each oral session. This has worked extremely well in the past meetings to highlight young investigators and to give them a platform to more fully discuss their work.

Indicate (if known) if there is a potential of a conflict with any other FASEB SRC or any other society or industry meeting. If yes, please explain the conflict in detail.

None we are aware of: Meetings on aging, no conflict. http://info-centre.jenage.de/ageing/meetings-calendar.html A meeting on protein folding in to be held in August 2015 – not a meaningful overlap with this conference http://www.biochemistry.org/Conferences/ProposeaConference.aspx No EMBO conference overlap http://www.embo.org/events

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Section 5: Scheduling & Location Preferences:

Select three (3) choices of dates from early June through the middle of October the year you wish to hold the conference. Conferences begin on a Sunday and conclude on a Friday.

Week 1: Aug. 9-Aug. 14 Week 2: Aug 16-21 Week 3: August 23-28

Check at least three (3) different venues for consideration. The venue checked in column “1” should be the most preferred. (Note: We will do our best to give you your first choice but it cannot be guaranteed.)

Note: NAD Metabolism and Sirtuins/HDACs are closely related. The 2015 FASEB meeting “NAD Metabolism and Signaling” co-organized by Vera Gorbunova, Paul Chang, Andreas Ladurner and Andreas Guse should not overlap with this meeting. The best strategy may be to have them back-to-back in Europe so that speakers from one can stay for the other. We should aim to coordinate timing of these two.

Selected Venues: Il Ciocco Resort, Barga, Italy (Late summer)* 1 Suzhou Conference Center, Shanghai, China 2 Nassau, Bahamas 3 *Because of the unusual number of European investigators in this field, the attendance is always higher at meetings held in Europe than at the US venues. The Il Ciocco Resort was recently renovated, the staff 1st class, and it is now a top-class meeting venue adored by the participants and the envy of those who weren’t invited. The atmosphere in this rural Italian setting is ideal to attract speakers, many of whom bring their families instead of declining the invitation to go elsewhere on vacation with their families during August. At this year’s meeting there was overwhelming support to hold the next meeting at Il Ciocco again, including those from the USA who say they accepted the invitation in large part because of this venue.

If the Il Ciocco Resort is not available, Shanghai would be an exciting option. We would aim to hold it at the new Suzhou Conference Center (http://www.csh-asia.org) where the Cold Spring Harbor Asia Conferences are being held regularly.

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Section 6: Justification

Histone deacetylases and sirtuins in biology, disease and aging

Submitted by Ming-Ming Zhou and David A. Sinclair

1. Explain why this topic is of high current interest to the scientific community? Histone deacetylases (HDACs) are vital regulators of fundamental cellular events, including cell cycle progression, stem cell functions, cell fate determination, cell differentiation, and the pathogenesis of many diseases (e.g., cancer). As such, protein acetylation is central to human diseases as diverse as neurodegenerative disorders, cardiac hypertrophy, cancer, HIV infection, and more generally the process of aging. More importantly, small molecule HDAC inhibitors and activators are currently in clinical trials for the treatment of leukemia and lymphoma, solid tumors, neuromuscular disorders, metabolic disorders and other diseases. In addition, the Sirtuins, a subclass of HDACs, have been shown to delay more than a dozen different diseases and extend lifespan in rodents. These enzymes are activated by resveratrol, one of the components in red wine that has been linked to increased health and lifespan in humans. Synthetic sirtuin activators are now in clinical trials, with early results showing promise. In addition, new ways to activate sirtuins (e.g. NAD precursors, CD38 inhibitors) are emerging as exciting new approaches to treating diseases. Therefore, a thorough understanding of HDACs is required, not merely for understanding the regulation of chromatin structure, gene regulation and protein function, but also because HDACs are intimately involved in normal and abnormal cellular processes that greatly impact human health. With the identification, isolation, cloning and functional characterization of 18 human HDAC enzymes (HDAC1-11 and SIRT1-7) and many acetyltransferases in the past decade, it is likely that the coming years will see a continued dramatic expansion in our knowledge of the biological roles of HDACs and protein acetylation. Covalent modification of proteins by acetylation of lysine residues has emerged during the past 15 years as a key posttranslational modification that rivals reversible phosphorylation as a major regulatory mechanism of cellular pathways. This is because lysine acetylation not only alters the charge of the side chain by neutralizing the basic charge, but lysine residues are also the sites of protein ubiquitylation to control protein stability, sumoylation to regulate protein functions, and methylation, which often provides docking sites for protein to protein interactions. Lysine side chains are also modified by newly emerging mechanisms such as succinylation. Acetyl groups must be removed from the lysine residue by HDACs as a prelude to further modification. Thus, acetylation regulates the most fundamental aspects of protein function. One measure of the importance of lysine acetylation is that evolutionary studies indicate that these targets for acetylation are more conserved than the targets of phosphorylation for many critical cellular regulators such as the p53 tumor suppressor. While much of the initial work focused on histone acetylation and its role in gene

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regulation and this work robustly continues, research on the acetylation of non-histone proteins has progressed rapidly and proteins important for controlling gene regulation, cell cycle progression, mitochondrial metabolism, and cell migration are acetylated. Sirtuins are NAD-dependent protein deacetylases and are involved in aging and metabolism. Proteomic surveys of protein acetylation using highly sensitive mass spectrometric approaches have identified more than 2000 acetylated proteins, and there is evidence that more acetylated substrates will be discovered in the future as the sensitivity of our tools increases and as acetylation is studied under an increasing variety of physiological and pathological conditions. Given the emerging evidence for a role for protein acetylation in the regulation of non-histone and non-transcriptional processes, we expect that reversible protein acetylation will grow into a major discipline in its own right and that this meeting will continue to be the premiere venue for this topic. The purpose of this meeting is to foster rapid exchange of the most recent findings and concepts on HDACs, HATs and protein acetylation. Topics to be covered include biological functions, mechanisms of action, structure, and regulation of HDACs and Sirtuins. HDAC inhibitors and activators of Sirtuins and the roles of these enzymes in human diseases will be thoroughly discussed. A session on drug development and clinical results will be included to allow the latest advances in human research to be presented and to encourage industry support of the meeting. In addition, we will devote an entire session to novel lysine (acyl) modifications (e.g., succinylation, malonylation, long chain fatty acylation), which are opening up new areas of biology and are some of the most exciting new avenues the field is taking, integrating mitochondrial metabolism (e.g. TCA cycle) and protein regulation by acylation. Inclusion of these topics will add an appropriate balance to our discussions on reversible protein acetylation as a major regulatory mechanism of protein function and biological processes. 2. Is this a rapidly growing field? In the past 15 years, there has been an explosion of work on protein acetylation that has been catalyzed by the identification of the first histone acetyltransferase, the first histone deacetylase, and the recognition that a small molecule that was progressing through preclinical trials as an anticancer agent was in fact a histone deacetylase inhibitor. In parallel work, the sirtuins, proteins shown to regulate aging, were shown to also possess deacetylase activity. Then in 2003, activators SIRT1 such as resveratrol from red wine sparked even more interest in acetylation in biology and disease. These events sparked 3 parallel tracks of research into the enzymes that catalyze acetylation, deacetylation, and how these enzymes can be manipulated therapeutically. The number of proteins that are regulated by these enzymes continues to climb from a handful 15 years ago (predominantly histones) to over 2000 currently. While the initial focus was on histone modifications, and extensive work continues in this vein, the 18 deacetylases are not only found in the nucleus. They are also in the cytoplasm and within key organelles (e.g., mitochondria). Gene deletion studies in simple and complex organisms demonstrate that these deacetylases regulate the most fundamental

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processes including metabolism, cell survival, cytoskeletal functions, DNA replication, and gene expression. At the 2013 meeting, we heard about new work identifying the drug binding and activation domain of sirtuins, and the requirement of substrate specificity. This work opens up new avenues to discover and develop small molecules that modulate sirtuins. In addition, we heard about new approaches to activating all of the sirtuins with a single molecule, so-called “pan-sirtuin” activators. Examples include NAD precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), as well as inhibitors of CD38, an enzyme that degrades NAD. These findings are now appearing in top journals (with papers in Nature, Science, Cell this year). The 2015 meeting will be the perfect time for leaders to present their latest findings about the biology, safety and efficacy of these molecules in mammals and in treating human diseases. The literature on protein acetylation dates to 1935, but only about 100 papers were published on the topic between before 1996. Since 1996 there has been a great expansion of the literature following the identification of the first histone acetyltransferase and histone deacetylase. A literature survey reveals that about 31,953 papers have been published on protein acetylation (9/14/13). In just the first 9 months of this year nearly 2300 papers have been published on this topic. The number of papers on Sirtuins continues to grow rapidly, with nearly 1000 per year and over 5000 papers already published. If you include work on resveratrol, a sirtuin activator, the number is over 10,000. These numbers should not be surprising given that that this field impacts diseases from cancer to neurological diseases and fields from metabolism to cancer, from stem cell biology to aging. A goal of this meeting is to provide a venue for the presentation of breakthrough discoveries and in-depth discussions of this rapidly moving and growing field so that information and advances in specific areas can be immediately disseminated and applied to new problems. Special emphasis will be placed on cultivating a collegial atmosphere between disciplines and encourage informal discussions that will lead to formal collaborations. The response from the participants of the fourth HDAC meeting held this past August was overwhelmingly positive. The attendees recognized the rapid expansion of this field and the need to convene again in 2015 to discuss advances that are ongoing in key areas, including new enzyme substrates and lysine modifications, the integration of pathways to coordinate physiological responses to food intake, infection, and age-related diseases. By 2015, the results from ongoing clinical trials will also be ready for dissemination. 3. Have there been previous conferences on this topic? The first FASEB HDAC meeting was held in June 2007 at Snowmass (88 participants), the second FASEB HDAC meeting was held in August 2009 in Lucca, Italy (108 participants), the third meeting was held in late June 2011 in Steamboat Springs (89 participants), and the fourth in Barga in August 2013 (105 participants). The participants overwhelmingly voted to have a fifth meeting on this rapidly expanding topic. The

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participants agreed with the continued expansion of topics that included significant number of talks on histone/protein acetyltransferases, as well as acetylation-mediated protein-protein interactions in addition to the deacetylases, all of which play an fundamental role in gene transcription, metabolism and aging, as well as related diseases. There was also enthusiasm for expanding talks on alternative lysine modifications such as succinylation and long-chain fatty acylation, as these modifications are regulated either directly or indirectly through the deacetylases. As far as we are aware, there are no existing conflicts with the preferred meeting times listed above. 4. How many participants are expected to attend? If the meeting is held in Europe (e.g., Lucca, Italy or a similar site), we expect to increase the number of participants to around 135. This is a reasonable estimate for a number of reasons: the venue is extremely popular (the most popular either of us have ever seen for a meeting), the economies of the US and Europe are improving, and we expect to raise significant funds to support travel. In addition, we both have considerable experience in organizing successful meetings and in fund raising. Dr. Sinclair, for example, has organized Gordon, Keystone and Banbury Conferences and every year organizes a 500 person meeting on aging (The Annual Glenn Symposium on Aging) and the 350 person meeting at Cold Spring Harbor on Aging (since 2008). Dr Zhou has also organized large scientific conferences including Biophysical Society’s Annual Meeting (over 5000 participants) and Thematic Meetings (200+ participants), as well as symposia covering the topics of epigenetics, and structural/chemical biology. We are well equipped to raise money on account of our connections to industry (we already have GSK support). By having a number of European investigators lead sessions, and focusing our fundraising efforts towards bringing junior scientists to the meeting from the U,S. we should further increase overall participation. By placing a focus on aging/metabolism, a very large and active field, we will have a much greater pool of potential participants than in previous meetings. If the meeting returns to the U.S. we would expect the size to increase be about 110. In addition, if the meeting takes place in Suzhou/Shanghai, China, it is expected that the overall attendance will be even higher with many new participants from the rapidly growing research community in the Asian/Pacific countries. 5. What percentage of women attended this conference (if it was previously held)? In the first meeting this percentage was 24.5%, the second meeting it was 39%, in the third meeting it was 32%, and in the fourth it was 28%. 6. In what ways will you recruit young investigators to attend and participate in the conference? We have attempted to identify outstanding young scientists in the preparation of our preliminary program to invite as speakers. As we have done successfully in the last

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meetings, we will select abstracts from outstanding young investigators that will be included in the program as 10 to 15 minute talks. Moreover, we have already talked with industry connections about fundraising to defray travel costs and waive the registration fees of a select number of graduate students and postdoctoral fellows. 7. How will you recruit and select new speakers? Our tentative program has been constructed with the goal of attracting the participation of at least 16 (44%) new speakers and 15 women (41%). The speakers listed on the program were selected in part in consultation with the session chairs. In selecting new speakers, we considered his/her scientific accomplishment and prominence in the HAT/HDAC/protein acetylation fields. In addition, we sought to increase the number of women represented and increase the number of European and non-US speakers. Importantly, we will continue to work to include women speakers, minority speakers and early stage investigators holding faculty positions. 8. From what sources and resources will you use to solicit funds for the conference? (Provide specifics). Several biotechnology and pharmaceutical companies have already expressed interest in supporting this meeting financially. We expect to solicit funds from Novartis, Merck, GSK, Pfizer, Abbott/Abbvie, Amgen, Syndax, Methylgene, MetroBiotech, Repligen, Cell Signaling Technology, Amphora, GenScript, and Wuxi Apptec. In addition, we hope to obtain support from NIH, NSF and CCSRI (Canada) through competitive conference grant mechanisms. We will approach the people who funded for the last meeting from a

number of sources including the NIH (NIA), the Evans Foundation, Gabrielle’s Angel’s

Foundation, Acetylon, Constellation. In addition, we will solicit funds directly from past participants of these meetings. We feel that the senior scientists will be willing to make donations so that needy students and postdocs can attend this meeting. In 2013, the

organizers raised $6,200 because they recognize the important impact of this meeting and will

use their own funds to make it happen. We will leverage the success of this effort to request matching funds from organizations and companies. The remaining funds will be derived from registration fees. 9. Which societies and disciplines will you attract to attend the conference? (Provide specifics). A broad audience ranging from basic scientists interested in gene regulation, chromatin, and protein modifications to investigators involved in the studies of aging, metabolism, cancer, cardiovascular disease, HIV infection, and neurodegenerative disorders will be interested in this meeting. We anticipate that attendance at this meeting will include scientists affiliated with the Federation of American Society for Experimental Biology (FASEB), the Gerontological Society of America (GSA), the American Society for Biochemistry and Molecular Biology (ASBMB), the American Association for Cancer Research (AACR), and the American Society for Microbiology (ASM). 10. Where will you advertise the conference? What types of media will you use to

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advertise your conference? (Provide specifics).

We will use direct emails to contact former attendees and other scientists with an interest in chromatin, histone modifications, metabolism, and diseases or processes regulated by protein acetylation. We expect that the meeting be broadly publicized in basic research-oriented journals such as Cell, Science, and Nature. If the budget allows, we would include additional advertisements in Molecular Cell, Cancer Cell and Cell Metabolism. We also suggest posting the conference information in the following websites: Science (sciencemeeting.org), Conference Alerts (conferencealerts.com), and FASEB (www.src.faseb.org). I will also advertise the meeting on the Glenn Labs website at Harvard and at the Cold Spring Harbor Conference on Aging next October, which I co-organize. 11. Are you planning on submitting a similar application to another organization for additional funding and sponsorship? If yes, please clarify.

Not at this point in time, but we will work with the leaders at FASEB Summer Research Conferences to put together the most attractive conference possible and to attract the resources necessary to do so.

BIOGRAPHICAL SKETCH Provide the following information for proposed network coordinators and members

Follow this format for each person.

NAME Sinclair, David A.

POSITION TITLE Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, and include postdoctoral training.)

INSTITUTION AND LOCATION DEGREE

(if applicable) YEAR(s) FIELD OF STUDY

The University of New South Wales BS 1991 Biochemical Sciences The University of New South Wales Ph.D. 1995 Medicine The Massachusetts Institute of Technology Postdoc 1996-99 Genetics of aging

A. Positions and Honors (chronological order) POSITIONS AND EMPLOYMENT: 1996 -1999 Helen Hay Whitney Postdoctoral Fellow, Massachusetts Institute of Technology 1999- 2004 Assistant Professor, Department of Pathology, Harvard Medical School 2004- 2008 Associate Professor, Department of Pathology, Harvard Medical School 2005-present Director, Paul F. Glenn Labs for the Biological Mechanisms of Aging 2008-present Full Professor (tenured), Department of Genetics, Harvard Medical School 2011-present Co-joint Professor, University of New South Wales, Sydney BOARD AND SOCIETY MEMBERSHIPS:

- Prizes/honors: Commonwealth Serum Laboratories Prize (1992); Thompson Prize, Australia (1994); Helen Hay Whitney

Postdoctoral Fellowship (1996-1999); Leukemia Society of America Special Fellowship (1999-2002); Ludwig Institute

Young Faculty Award (2000-2001); American Federation for Aging Research Fellowship (2000-2002); Stewart Trust

Career Development Award (2001); Ellison Medical Foundation New Scholar (2001-2005); Genzyme Outstanding

Achievement in Biomedical Science Award (2004); Bright Sparks Award (2006); BioInnovator of the Year (2006); Ellison

Medical Foundation Senior Scholar (2007-11); Excellence in Teaching Award, Harvard Medical School (2008); David

Murdock-Dole Lectureship (2008); Fisher Lectureship, UCLA (2010); Nathan Shock Award for Aging Research, NIH/NIA

(2010); The Dean’s Lecture, UNSW, Sydney (2011); NIH/NIA MERIT Award (2012).

- Reviewer: NIA and DOD (2008, 2010-11); Committee Chair, Applicants to Foundations, Harvard (2008- ); Permanent

reviewer, NIA (CMAD) study section (2011- )

- Conference organizer: Glenn Symposium on Aging, Harvard Medical School (2005- ); Gordon Aging Conference

(2008); Sirtuin Banbury Meeting, NY (2009); Keystone Aging Meeting (2009); Cold Spring Harbor Aging Meeting (2008- ).

- Co-founded the journal Aging, co-chief editor (2010- )

-Co-founder & advisor: Sirtris Pharmaceuticals (2005 - ), Genocea Biosciences (2006 - 2008), Cohbar (2010 - ),

Ovascience (2012 - ), MetroBiotech (2013 - ).

B. Selected publications (from a total of 105)

Anderson, R., Bitterman, K., Wood, J., Medvedik, O. and Sinclair, DA. (2003) Nicotinamide and Pnc1 govern lifespan extension by calorie restriction in S. cerevisiae. Nature, 2003; 423:181-185

Anderson, RA., Latorre-Esteves, M., Neves, A., Lavu, S., Taylor, C., Howitz, KT., Santos, H., Sinclair, DA. Lifespan extension by calorie restriction is independent of NAD fluctuation. (2003) Science 302:2124-2126.

Howitz, KT., Bitterman, KJ., Cohen, HY., Lamming, DW., Lavu, S., Wood, JG., Zipkin, RE., Chung P., Kisielewski, A., Zhang, L., Scherer, B., Sinclair DA. (2003) Small molecule sirtuin activators that extend S. cerevisiae lifespan. Nature,

425:191-196

Cohen, HY, Miller, C, Bitterman, KJ, Wall, NR, Hekking, B, Kessler, B, Gorospe, M, de Cabo, R.,Sinclair, DA. (2004) Calorie restriction promotes cell survival by inducing SIRT1. Science, 305:390-2. PMID:15205477

Wood, J, Rogina, B, Lavu, S, Howitz, KT, Helfand, SL, Tatar, M, Sinclair, DA. (2004). Sirtuin activators mimic

calorie restriction and delay aging in metazoans. Nature, 430:686-9. Lamming, D, Latorre-Esteves, M, Medvedik, O, Wong, S.N., Tsang, F.A, Wang, C, Lin, S-J, Sinclair, DA (2005) HST2

mediates SIR2-independent lifespan extension by calorie restriction. Science, 309(5742):1861-4. PMID:16051752 Baur, J, Pearson, K., 25 authors, deCabo, R, Sinclair, DA. (2006) Resveratrol increases health and survival of mice on a

high calorie diet. Nature 444(16): 337-342. Milne, J., Sinclair, D., Olefsky, J., Jirousek, M, Westphal, C. (2007) Novel Small Molecule Activators of SIRT1 as

Therapeutics for Treatment of Type 2 Diabetes. Nature, 450(7170):712-6. PMCID: PMC2753457 Yang, HY, Yang, T, Baur, JA, Perez, E, Matsui, T, Carmona, JJ, Lamming, DW, Souza-Pinto, NC, Bohr, VA, Rosenzweig,

A, de Cabo, R, Sauve, AA, Sinclair, DA. (2007) Nutrient-regulated NAD+ levels in mitochondria dictate cell survival.

Cell, 130(6):1095-107. Pearson, K*, Baur, J*, Lewis, KN, Peshkin, L, Price, NL. Navas, P., Ingram, D., Wolf, N., Ungvari, Z, Sinclair, DA*, de

Cabo, RA* (2008). Resveratrol delays age-related deterioration and mimics aspects of dietary restriction in mice on a standard diet. Cell Metabolism, 8(2):157-68.

Oberdoerffer, P., Michan, S. McVay, M. - 8 authors - Mills, K., Bonni, A., Yankner, B., Scully, R., Prolla, TA., Alt, FW. and David A. Sinclair, D. (2008). DNA damage-induced alterations in chromatin contribute to genomic integrity and age-related changes in gene expression. Cell,135(5):907-18.

Minor, R., Baur, J, Gomes, A., Price, N., Hubbard, B., Westphal, C., Ellis, J., Vlasuk, G., Sinclair, D.A. deCabo, R. (2011) SRT1720 improves survival and healthspan of obese mice. Nature Reports 1, 70. PMC3216557

Ramadori, G., Fujikawa, T., Anderson, J., Berglund, E.J., Frazao, R., Michan, S., Vianna, C., Sinclair,D.A., Elias, C. and Coppari. R. (2011) SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metabolism, 14(3):301-12 P

Price, N.L., Gomes, A.P., Ling, A.J., Martin-Montalvo, A, North, B.J., Hubbard, B.P., Agarwal,B. Davis,J., Varamini, B. Hafner, A., Rolo,A., Palmeira,C.M., de Cabo,R., Baur,J., and Sinclair, D.A. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metabolism, 15(5): 675-90

Armour, SM., Bennett, EJ., Braun, CR., Zhang, XY., McMahon, SB., Gygi, SP., Harper, JW., and Sinclair, DA. (2013). A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Molecular Cell Biology, 33(8):1487-502. PMID: 23382074.

Biason-Lauber, A., Boni-Schnetzler, M., Hubbard, BP., Bouzakri, K., Brunner, A., Cavelti-Weder, C., Keller, C., Meyer-Boni, M., Meier, DT., Brorsson, C., et al., Sinclair, DA., and Donath, MY. (2013) Identification of a SIRT1 mutation in a family with type 1 diabetes. Cell Metabolism, 17(3):448-55. PMID: 23473037

Lai, L., Yan, L., Gao, S., Hu, CL., Ge, H., Davidow, A., Park, M., Bravo, C., Iwatsubo, K., Ishikawa, Y., Auwerx, J., Sinclair, DA, Vatner, SF., and Vatner, DE. (2013) Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway. Circulation, PMID: 23526361

Tilly, JL. and Sinclair, DA. (2013) Germline energetics, aging, and female fertility. Cell Metabolism, 17(6):838-50. Hubbard, BP., Gomes, AP., Dai, H., Li, J., Case, AW., Considine, T., Riera, TV., Lee, JE., E, Sy., Lamming, DW.,

Pentelute, BL., Schuman, ER., Stevens, LA., Ling, AJ., Armour, SM., Michan, S., Zhao, H., et al., Hamuro, Y., Moss, J., Perni, RB., Ellis, JL., Vlasuk, GP., and Sinclair, DA. (2013). Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science, Vol. 339: 1216-1219.

Martin-Montalvo, A., 23 authors, Sinclair, D.A., Wolf, N.A., Spindler, S., Bernier, M. and de Cabo, R. (2013) Metformin improves healthspan and lifespan in mice. Nature Communications, in press

Schmeisser, K., Mansfeld, J., Kuhlow, D., Weimert, S., Zarse, K., Prieve, S., Heiland, I., Birringer, M., Groth, M., Segref, A., Werner, C., Schmeisser, S., Schuster, S., Pfeiffer, A., Guthke, R., Platzer, M., Hoppe, T., Cohen, C., Sinclair, D.A., Ristow, M. (2013) The niacin metabolite 1-methylnicotinamide extends lifespan in a PARP/sirtuin-dependent manner by including a transient redox signal. Nature Chemical Biology in press.

C. Current and anticipated research support R01 AG028731 (PI: Sinclair, D) 9/1/2012 - 8/31/2017 1.2 calendar Sirt1 as a regulator of health and lifespan of mammals $ US 130,000 This study is to identify mechanisms by which mitochondria are maintained during aging. A screen of the human genome identified ~80 regulatory genes, including a group of secreted factors. Glenn Laboratories Fund (PI: Sinclair, D) 1/1/2010 - 12/31/2015 No time allocation Studies of basic mechanisms of aging $ US 150,000 Funds are for Sinclair lab in admin support and some mouse costs, to recruit faculty members to Harvard, an annual symposium, and support an animal metabolic and behavioral core facility. Juvenile Diabetes Research Foundation (PI: Donath, M) 1/12/2011 – 1/12/2013 SIRT1 in Type I diabetes $ US 120,000 This study is to understand the role of SIRT1 in autoimmune disease and Type 1 diabetes, to characterize affected patients carrying the L107P mutation and understand why this leads to disease.

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME Ming-Ming Zhou

POSITION TITLE Professor and Chairman

eRA COMMONS USER NAME (credential, e.g., agency login) zhoum2 EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)

INSTITUTION AND LOCATION DEGREE (if applicable) MM/YY FIELD OF STUDY

East China Univ. of Science & Technology, PRC B.S. 1984 Chemical Engineering Michigan Technological University M.S. 1988 Chemistry Purdue University Ph.D. 1993 Chemistry

A. Personal Statement My research interest is directed at better understanding of the fundamental molecular mechanisms of epigenetic control of gene regulation using combined structural/chemical biology and molecular/cell biology methods. My major research contributions include the discovery of the bromodomain as the acetyl-lysine binding domain in gene transcription (Nature, 1999), the double PHD finger of DPF3b as a first alternative to the bromodomain for acetylated histone binding in gene transcription (Nature 2010), and the PAZ domain as the RNA binding domain in RNAi (Nature 2003). Our work addresses the role of lysine acetylation (Mol. Cell 2002, 2004; NSMB 2008; PNAS 2012), lysine methylation (Nature SMB. 2003, 2005; JMB 2006; Nature Cell Biol. 2008; Mol. Cell 2010; PNAS 2010), and molecular interplay between histone methylation and DNA methylation in gene transcriptional silencing. Our research in rational design of chemical probes to modulate bromodomain/acetyl-lysine mediated molecular interactions in gene transcription has led to our discovery of HIV Tat/human co-activator PCAF interaction as a potential novel anti-HIV therapy target (Mol. Cell 2002; JACS 2005, 2010; JMC 2007, 2009), for which I received a GlaxoSmithKline Drug Discovery & Development Award in 2003. Our recent discovery of a novel viral gene silencing mechanism (Nature Cell Biol. 2008) has led to our research on development of an innovative gene transcriptional silencing technology based on histone lysine methylation.

B. Positions and Honors PROFESSIONAL EXPERIENCE 1993 – 1996 Postdoctoral Fellow (Advisor: Stephen W. Fesik), Abbott Laboratories, Chicago, IL 1997 – 2000 Assistant Professor, Structural Biology Program, Department of Physiology & Biophysics,

Mount Sinai School of Medicine (MSSM), New York, NY 2001 – 2004 Associate Professor, Structural Biology Program, Department of Physiology & Biophysics, and Department of Oncological Sciences (then the Ruttenberg Cancer Center), MSSM, NY 2004 – Professor, Departments of Structural and Chemical Biology (formerly Physiology & Biophysics), Oncological Sciences, and Pharmacology & Systems Therapeutics, MSSM, NY 2004 – Director, Translational Chemical Biology Center, Mount Sinai School of Medicine, NY 2005 – Dr. Harold and Golden Lamport Professor, and Chairman, Department of Structural and

Chemical Biology, Mount Sinai School of Medicine, NY 2009 – Co-Director, Experimental Therapeutics Institute, Mount Sinai School of Medicine, NY

OTHER PROFESSIONAL ACTIVITIES (partial list) Director, Board of Directors, New York Structural Biology Center (2004 – present); Consultant, Research Institute of Molecular Pathology, Vienna, Austria (2001); Co-Chair, 2009 Program Committee for 53rd Annual Meeting, Biophysical Society (2007–2009); Session Chair, The 2009 ASMBM Annual Meeting, “Chromatin Regulation,” New Orleans, LA (04/2009); Cancer Research, Associate Editor (2008 – 2013) Journal of Molecular Cell Biology, Editorial Board (2009 – present); ACS Medicinal Chemistry Letters, Editorial Board (2010 – present); Faculty of 1000 on “Structure, and Transcription and Translation”, Contributing Member (2010 – present). Journal of Cancer Immunology – Editorial Board (2012 – present).

HONORS & AWARDS 1999 – 2001 American Cancer Society Young Investigator Award 2003 GlaxoSmithKline Drug Discovery and Development Award 2006 Dr. Harold and Golden Lamport Professorship in Physiology and Biophysics 2009 Elected to the Academy of Sciences & Arts at Michigan Technological University 2012 Elected to a Fellow of American Association for the Advancement of Science C. Selected peer-reviewed publications (from a total of over 130 papers) 1. Zhang, G., Liu, R., Zhong, Y., Plotnikov, A.N., Zhang, W., Zeng, L., Rusinova, E., Gerona-Nevarro, G.,

Moshkina, N., Joshua, J., Chuang, P.Y., Ohlmeyer, M., He, J.C., & Zhou, M.-M. (2012) Down-Regulation of NF-kB Transcriptional Activation in HIV-Associated Kidney Disease by BRD4 Inhibition. Journal of Biological Chemistry. 287(34): 28840-51. Epub 2012 May 29. PMCID: PMC3436579.

2. Gerona-Navarro, G., Rodríguez-Fernández, Y., Mutjaba, S., Frasca, A., Patel, J., Plotniov, A.N., Osman, R. & Zhou, M.-M. (2011) Rational Design of Cyclic Peptide Modulators of the Transcriptional Coactivator CBP: A New Class of p53 Inhibitors. Journal of Am. Chem. Soc., 133(7): 2040-2043. PMID: 21271695. Epub 2011 Jan. 27. PMCID: PMC3047509.

3. Borah, J.C., Mujtaba, S., Karakikes, I., Zeng, L., Muller, M., Zhang, W., Gerona-Navarro, G., Hajjar, R.J., & Zhou, M.-M. (2011) A Small Molecule Binding to the Co-Activator CREB-Binding Protein Blocks Apoptosis in Ischemic Cardiomyocytes. Chemistry & Biology 18(4):531-41. PMID: 2153899. 2011 Apr 22. PMCID: PMC3103858.

4. Wei, H., & Zhou, M.-M. (2010) Dimerization of a Viral SET Protein Endows its Function. Proc. Natl. Acad. Sci. USA, 107(43): 18433-8. Epub 2010 Oct 11. PMID: 20937900.

5. Zeng, L., Zhang, Q., Li, SiDe, Plotnikov, A.N., Walsh, M.J., & Zhou, M.-M. (2010) Mechanism of Multivalent Histone Interactions with Human DPF3b in Gene Transcription. Nature 466, 258-262. PMID: 20613843.

6. Yap, K.L., Li, S., Munoz-Cabello, A.M., Raguz, S., Zeng, L., Mujtaba, S., Gil, J., Walsh, W.J., & Zhou, M.-M. (2010) Molecular Interplay of the Non-coding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a. Molecular Cell, 38(5): 662-674. PMID: 20541999

7. Charlop-Powers, Z., Zeng, L., Zhang, Q., & Zhou, M.-M. (2010) Structural Insights into Selective Histone H3 Recognition by the Human Polybromo Bromodomain 2. Cell Research 20(5):529-38. PMID: 20368734. NIHMS224907.

8. Mujtaba, S., Manzur, K.L., Gurnon, J.R., Kang, M., Van Etten. J.L. & Zhou, M.-M. (2008) Epigenetic Transcription Repression of Cellular Genes by a Viral SET Protein. Nature Cell Biology 10, 1114-1122. PMID: 18711358.

9. Pan, C., Mezei, M., Mujtaba,S., Muller, M., Zeng, L., Li, J.M., Wang, Z.Y., & Zhou, M.-M. (2007) Structure-Guided Optimization of Small Molecules Selectively Inhibiting Human Immunodeficiency Virus 1 Tat Association with the Human Coactivator p300/CREB Binding Protein-Associated Factor. Journal of Medicinal Chemistry 50, 2285-2288.

10. Zeng, L., Li, J., Muller, M., Yan, S., Mujtaba, S., Pan, C., Wang, Z.Y., & Zhou, M.-M. (2005) Selective Small Molecules Blocking HIV-1 Tat and Coactivator PCAF Association. J. Am. Chem. Soc., 127, 2376-2377.

11. Mujtaba, M., He, Y., Zeng, L., Yan, S., Plotnikova, O., Sachchidanand, Sanchez, R., Zeleznik-Le, N., Ronai, Z., & Zhou, M.-M. (2004) Structural Mechanism of the Bromodomain of the Coactivator CBP in p53 Transcriptional Activation. Molecular Cell 13, 251-263. PMID: 14759370.

12. Manzur, K., Farooq, A., Zeng, L., Plotnikova, O., Koch, A. W., Sachchidanand, & Zhou, M.-M. (2003) A Dimeric Viral SET Domain Methyltransferase Specific to Lys27 of Histone H3. Nature Structural Biology 10, 187-196.

13. Mujtaba, S., He, Y. Zeng, L., Farooq, A., Carlson, J., Ott, M., Verdin, E., & Zhou, M.-M. (2002) Structural Basis of HIV-1 Tat Recognition by P/CAF Bromodomain, Molecular Cell 9, 575-586. PMID: 11931765.

14. Yan, K.S., Yan, S., Farooq, A., Han, A., Zeng, L., & Zhou, M.-M. (2003) Structure and Conserved RNA Binding of the PAZ Domain. Nature 426, 469-474. PMID: 14615802.

15. Dhalluin, C., Carlson, J.,Zeng, L., He, C., Aggarwal, A.K., & Zhou, M.-M. (1999) Structure and Ligand of a Histone Acetyltransferase Bromodomain. Nature 399, 491-496. PMID: 10365964.

D. Research Support − Research Projects Ongoing or Completed During the Last 3 Years

Ongoing Research Support R01HG004508-04 (Zhou, PI) 09/24/2008 – 01/31/2015 NIH/NHRGI “Chemical Genomics Paradigm for Epigenetics Regulation” This project is to develop new methodology and chemical tools to study protein functions in gene regulation.

P01CA80058-11 (S. Aaronson, PD) 07/01/2010 – 06/30/2015 NIH/NCI “p53 Regulators and Effectors” “Molecular Interactions and Regulation of p53”, Project #2 (PI: Zhou; Co-PI: J. Manfredi) This project is to study molecular interactions of human tumor suppressor p53 in response to DNA damage.

R33DA029963-04 (M. Ohlmeyer; Zhou, mPIs) 08/01/2010 – 07/31/2015 NIH/NIDA “Small Molecule Libraries Targeted to CBP and Attenuation ΔfosB Expression” This project aims to develop small molecule libraries of chemical ligands that are designed to inhibit CBP function in transcriptional activation of ΔfosB.

R01CA154809-02 (M. Walsh; & Zhou, mPIs) 01/01/2011 – 12/31/2015 NIH/NCI “Non-coding RNAs for epigenetic transcriptional silencing in prostate cancer” This project aims to investigate the mechanistic role of long non-coding RNAs in epigenetic control of transcriptional silencing of Hox genes in prostate cancer.

R01CA87658-12 (Zhou, PI) 04/02/2012 – 03/31/2017 NIH/NCI “Structure and Mechanism of Protein Modules in Chromatin Biology” This project is to study structural and biochemical basis of protein-protein interactions in chromatin biology.

(Zhou, PI) 07/01/2011 – 06/30/2014 The Samuel Waxman Cancer Research Foundation “Modulating Transcriptional Repressor Sin3A for Targeted Epigenetic Cancer Therapy” This project aims to develop small molecule modulators for Sin3A using structure-guided approaches.

Completed Research Support #C024358 (Zhou, & Walsh, M. co-PIs) 01/01/2009 – 12/31/2011 NYSTEM “Molecular Deciphering of Stem Cell Epigenetic Silencing” This project is to investigate the mechanistic functions of chromatin modifications in transcriptional gene silencing during stem cell self-renewal and differentiation.

R01GM073207-04 (Zhou, PI) 09/01/2006 – 08/31/2010 NIH/NCI “Structure and Mechanism of Pathogen SET Domain HKMTs” This project investigates the structure-mechanism of histone lysine methyltransferases.

Course Evaluation 2013 Science Research Conferences

Histone Deacetylases Sirtuins and ReversibleAcetylation in Signaling and Diseasepresented 8/18/201329 forms submitted

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Forms

Section 1 - Scientific Content

General Sessions

The most important areas of current active research were adequately discussed. 4.8

There was a sufficient amount of unpublished research presented. 4.2

The conference helped you generate new ideas for research. 4.6

There was adequate time provided for invited presentations and short talks selected from submitted abstracts. 4.4

The discussion periods were utilized effectively. 4.6

Poster Sessions

The time allocated for poster sessions was effective. 4.4

I am satisfied with the contribution of the poster sessions to the conference. 4.4

Scientific Content - Overall

Overall, I am satisfied with the scientific content. 4.8

What kinds of sessions would you like to see included at future conferences?

a bit more chemical biology

Translation to the clinic

lung cancer research

I would like to see more grouping of speakers with similar topics. For example, put those speaking about roles of HDACs in the CVsystem together. It seemed like everything was all mixed together this time.

Section 2 - Management

Program Management & Organization

How satisfied were you with the coordination and organization of the scientific program? 4.6

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How satisfied were you the representation of international scientists in this field participating? 4.6

How satisfied were you with the conference materials provided? 4.6

Did you feel the length of conference sessions were too long, just about right, or too short? 2.6

(3=Too long; 2= Just about right; 1=Too short)

Logistics Management & Organization

How satisfied were you with the registration and abstract submission process? 4.6How satisfied were you with the information found on the FASEB SRC website and from emails sent by the FASEB SRCOffice? 4.5

Overall Management & Organization

The conference was well organized. 4.7

Conference onsite staff member was helpful and courteous. 4.7

Overall, I was satisfied with the conference facilities. 4.8

Where would you like to see future SRCs take place?

Europe...same place

more U.S.

I wish we could keep coming back.

in the US

Perhaps a free afternoon is not required every day and instead it would be good to have some time in the evening to socialise.

same place

Europe- Asia

I loved the Barga location in Italy

USA/Europe, although a different location.

Greece, France, Spain, Australia

Europe

I like the site in Italy, but I would also prefer that this conference be held alternately in Europe and the US. It was too expensive tobring students from the US to Italy. If it comes back to the US next time, I would prefer the Steamboat Springs site over other USsites.

This site was great.

In Asia

Il Ciocco (Barga)

Which months are more convenient for you to attend a conference?

June - August: 22 (84.6%)

September - November: 2 (7.7%)

March - May: 1 (3.8%)

December - February: 1 (3.8%)

Overall, how would you rate the FASEB SRC Staffs' professionalism and responsiveness to your questions and concerns? 4.7

Comments:

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This was one of the best venues and conferences I have attended

Two comments: First, the bus reservation link on the FASEB website brought us to a pdf that we had to Fax to the FASEB office. Itwas useless because there were no times designated for the bus from Pisa to the conference site. This needs to be improved. Second,the conference room at the Italy site causes an echo when the audio system is used. It was challenging to understand everythingsaid, especially with speakers that spoke English with a heavy accent.

Section 3 - General Information

Approximately how many conferences of this type do youattend annually?

1-2 per year: 19 (65.5%)

3-4 per year: 6 (20.7%)

5-6 per year: 2 (6.9%)

More than 6 per year: 1 (3.4%)

Don't usually attendconferences: 1 (3.4%)

Do you plan to attend this conference again in 2 or 3 years?

Yes: 27 (93.1%)

No: 2 (6.9%)

Would you recommend this conference to others?

Yes: 28 (96.6%)

No: 1 (3.4%)

Not Sure: 0 (0%)

No response: 0 (0%)

How would you rate this conference compared toother conferences of this type that you haveattended?

4.6

How did you learn of this conference?

By Invitation: 11 (37.9%)

Co-Worker: 10 (34.5%)

Internet: 5 (17.2%)

FASEB Emails: 2 (6.9%)

Other: 1 (3.4%)

FASEB Mailings: 0 (0%)

FASEB Journal: 0 (0%)

ExperimentalBiology/Neuroscience/Cell

Biology:0 (0%)

If other, please specify:

My supervisor toldabout it to me: 1 (50%) I know the former

meeting organizer: 1 (50%)

Please indicate your age group:

20's: 5 (17.2%)

30's: 7 (24.1%)

40's: 8 (27.6%)

50's: 8 (27.6%)

60's: 1 (3.4%)

70's: 0 (0%)

In what ways could this conference be improved?

The organization was very good but the timing of the sessions was a bit strange. I think that after-dinner session are not very good.Maybe 1 session in the morning and 1 in the late afternoon (5-8:00 PM) would be better.

The talks tended to run too long and there wasn't enough time for question and discussion. Speakers has to be encouraged to keepto their time and there should be a clock or indicator of how they are doing with time while they are presenting. It would be better tohave free internet in the rooms than in the meeting room.

Stick to timings- sessions often ran an hour late due to speakers not factoring in time for questions. This should be rectified in thefuture.

Make sure it alternates between the US and overseas sites.

Speaker talks should be limited to 20 minutes with 10 minutes for questions. This should be told to speakers ahead or time andadhered to at the conference.

Evening session was difficult to stay motivated for. I would prefer to have a few afternoon talks, followed by a later dinner and then a

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few more talks ending by ~8pm. The talks on the last day (Friday) were scheduled after most people left on the conference organizedbusses. Those talks could have been distributed throughout the week (M-Th) and have the conference end after the Th eveningsession.

not reallyactually this is a perfect conference for me, small but many experts from the field in a perfect place.

Make it 1 day shorter, as there is a little bit too much free time, overall, the conference takes too long for the number oftalks/posters. That is my main complaint.

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Final Report HDACs, Sirtuins and Reversible Acetylation in Signaling and Disease

Il Ciocco Resort, Barga, Lucca, Italy Aug. 18-23, 2013

Organizers: Scott Hiebert Melanie Ott The biennial meeting of investigators focused on histone deacetylases and protein acetylation met in August of 2013 at the Il Ciocco Resort to share their latest discoveries. The study of protein acetylation is exploding as the links between the regulation of metabolism, gene expression, and aging come into focus. The field continues to make remarkable progress in expanding the diversity of research areas. The new areas opened up during this meeting included new lysine acylation linking fatty acids to proteins that can be cleaved by Sirtuins, remarkable progress on the cellular signaling pathways that are regulated by Sirtuins and HDACs, and conversely the diverse signaling pathways that end in altered lysine acetylation. In addition, the clinical translation of basic discoveries is accelerating such that the basic science is now being informed by clinical trials and data from human studies.

The meeting began on Sunday evening with a keynote address by Dr. Eric Verdin from the Gladstone Institute at UCSF. Dr. Verdin began his address by providing a historical perspective of the field, highlighting the exponential growth in the number of publications on protein deacetylases in the past 2-3 years. He then highlighted work from his lab on both HDACs and Sirtuins, emphasizing that HDAC inhibitors are produced naturally in our bodies and showing dramatic changes in protein acetylation upon production of these small molecules.

Over the following 5 days, we heard 25 min talks from 32 invited speakers, including 9 European speakers and one from Australia. We also included a Wednesday afternoon session featuring 3 full-length talks from leaders from the pharmaceutical industry who are attempting to target HDACs and Sirtuins in the clinic. An additional three full-length talks were also selected from the abstracts as well as 22 short talks, which provided a rich source of late breaking new information. The statistical breakdown of the speakers indicated that 17 were women (28%), 17 were from Europe (28%), 2 were from Australia, 1 was from Canada, and 3 were under represented minorities. 57% of the speakers had not given oral presentations at the past 2 meetings, which allowed us to bring many new investigators into the meeting.

We also held two 2-hour poster sessions in which 51 posters were presented. The program in which the oral presentations were arranged in the order presented, and the poster abstracts were arranged in numerical order facilitated the discussions. These sessions were very well attended and were remarkable sessions in that each poster had many scientists gathered around for the entire time. In fact, the discussion was so robust that it continued for 15-20 min past the end time, and only the need to move to dinner ended the discussions. This level of interest and discussion was emblematic of the meeting.

The 10 major sessions and the keynote lecture covered a diverse range of basic, translational, and clinically relevant information. The work highlighting Sirtuins focused on how Sirtuins monitor metabolic states in the cytoplasm, the mitochondria and the nucleus to execute physiological changes. Sirtuins do this by changing their activity in response to altered NAD levels. Moreover, results on small molecule activators of Sirtuins indicated that these compounds act on only a portion of Sirtuin targets and raise the possibility that endogenous activators may exist in addition to NAD. Transgenic over expression of Sirtuins as well as gene deletion showed the key role that Sirtuins play in the response to metabolic stress as well as

how these enzymes control key physiological response such as circadian rhythms. In fact, a brain-specific transgenic mouse was used to suggest that the increase in life span observed from the activation or over expression of Sirtuins was linked to the regulation of circadian rhythms. Finally, in a remarkable series of experiments, it was reported that Sirtuins do not just target Lysine acetylation, but also affect other Lysine acylations including succinylation, which is relatively specific to Sirt5.

For the non-Sirtuin HDACs, there was a great deal of excitement centered on the linking of the regulation of these enzymes to inositol phosphate signaling. While IP3 did not activate these enzymes, IP4 as well as variations of these molecules and IP5, IP6 and pyrophosphates worked well. Structurally, these molecules lie at the interface of co-repressors and class 1 HDACs. Intriguingly, not all class 1 HDAC complexes were sensitive to IP signaling, leading to the speculation that the Sin3A complex may sense other signaling pathways. Nevertheless, it appears that several class 1 HDACs act downstream of calcium changes that signal via IP3 IP4. Importantly, proteomic approaches demonstrated robust and rapid changes in response to EGF and IGF-1 signaling. These changes were similar to those seen in Ser and Thr phosphorylation. As such, the dynamic changes that occur in lysine acetylation open an entire new frontier in signaling. Moreover, these HDACs also act in the nucleus to alter gene expression and to control DNA replication. Thus, these are key enzymes that integrate extra-cellular and intracellular signals to control gene expression, cell proliferation, and stem cell functions.

The intimate and collegial of this meeting provided an ideal format for robust discussions. Each session chair struggled with keeping the sessions on time due to the remarkable level of discussion in the question and answer period. These discussions continued in an informal manner in the conference hall for up to an hour after the session had finished and then spilled over to the meals. An especially important aspect of this meeting is that all of the participants stayed at the resort and shared each meal. Thus, the students and fellows had the opportunity to share a table with the world’s expert in their field. An important aspect of this meeting was the venue. The Il Ciocco resort was renovated recently and is now a top-flight meeting venue. The relaxed atmosphere in this rural Italian setting was ideal to allow robust discussion and to bring together U.S. and European scientists to share knowledge.

Funding for this meeting was obtained from a number of sources including the NIH (NIA), the Evans Foundation, Gabrielle’s Angel’s Foundation, Acetylon, Constellation, and Glaxo Smith Cline. Importantly, the investigators in the field contributed over $6,200 to hold this meeting. Thus, the attendees recognize the impact of this meeting on their research and supported this meeting with their own funds to make it happen.

On Thursday at noon we held a business meeting to elect new organizers and to identify the location for the next meeting. There was unanimous support to hold the meeting again in 2 years. Perhaps due to the success of the venue, the attendees voted to return the meeting to Europe in 2 years, possibly returning to the Il Ciocco location. Four investigators allowed their names to be placed in nomination as organizers for the next meeting and Dr. David Sinclair (Harvard) was voted to be the organizer with Dr. Ming-Ming Zhou (Mt. Sinai) as co-organizer. Dr. Melanie Ott agreed to serve as Emeritus Organizer to provide continuity. Dr. Sinclair has organized many Keystone conferences in the past and has all of the expertise and organizational skills needed to make the next meeting a success.

Overall, the organizers were extremely pleased with the meeting. The level of discussion and collaboration were unmatched and the growth of the field is breathtaking. Without doubt the 2015 meeting will be even more enlightening as to the role of Sirtuins and HDACs in signaling and disease.

Year# of

Applicants# of

Participants Commercial Non-Commercial Government Total Raised2007 94 88 35,310.19$ -$ 58,620.38$ 2009 111 109 49,000.00$ 15,000.00$ 64,000.00$ 2011 91 89 503.28$ -$ 503.28$ 2013 106 106 4,000.00$ $20,500.00 7,000.00$ 38,500.00$

ATTENDANCE FUNDING

HDACs, Sirtuins, and Reversible Lysine ModificationsComparison of Previous Conferences

Year Name Affiliation2007 Ed Seto H. Lee Moffitt Cancer & Research Institute

Xiang-Jiao Yang McGill Univ.

2009 John Denu Univ. of WisconsinTso-Pang Yao Duke Univ.

2011 Erik Verdin Gladstone Institute of Virology and ImmunologyJames Davie University of Manitoba

2013 Scott Hiebert Vanderbilt University School of MedicineMalanie Ott Gladstone Institutes, University of San Francisco

HDACs, Sirtuins, and Reversible Lysine ModificationsPast Conference Organizers

December 5, 2011 Dr. Melanie Ott University of California San Francisco Gladstone Institutes 1650 Owens Street San Francisco, CA 94158 USA Re Proposal #: 13-13 Dear Dr. Ott: We would like to thank you for submitting a proposal for the 2013 FASEB Summer Research Conference series. The Advisory Committee has carefully reviewed the proposal entitled, "Histone Deacetylases, Sirtuins and Reversible Acetylation in Signaling and Disease". They have requested you make revisions to your program before they make their final decision. In order for the conference to be approved for the 2013 conference series, the committee requires the following improvements be made and met. The committee would like you to respond by Thursday, December 15, 2011 to the following comments/concerns before they will make a decision:

• The committee asks that you form a plan for continuity in leadership. A successful plan includes a co-organizer of the conference becoming the main organizer for the next conference. A leadership plan ensures the conference’s continued success in terms of the program, advertising, and fundraising.

• The committee asks that you address the recent drop in fundraising

and create a plan to increase support. The drop in fundraising is as follows:

Year

Non-Commercial Total Raised Commercial Government

2009 $49,000.00 $- $15,000.00 $64,000.00 2011 $503.28 $- $- $503.28

Fundraising is key to reimbursing speakers and assisting junior investigators and students.

• The committee notes that your conference topic is similar to conferences that may conflict with yours. Please detail how you will distinguish your program from similar conferences.

Dr. Ott Page 2 The committee requests that you make every effort to include young investigators (poster presentation or a short talk) as early as possible within the conference agenda. This will have an enormous impact on one’s experience at the conference. This will also allow other participants to learn early on about their work and will then greatly increase interaction. We will soon begin the process of developing the conference schedule and will let you know the location and date of your conference as soon as this has been decided. Please keep in mind, location and date preferences are not guaranteed however we do our best to give you your first choice. In February, an Organizer Manual will be posted at our website (www.faseb.org/SRC) to assist you in your conference planning efforts. Please be aware that by agreeing to be an Organizer/Co-organizer of a FASEB Summer Research Conference, that should you decide to cancel the conference for any reason, you will be held responsible for any fees related to the cancellation (i.e., fees charged by the host location). The Summer Research Conferences have been very successful over the years due to the commitment and dedication of the Organizers. On behalf of the Federation and the Summer Research Conferences Advisory Committee, your efforts in contributing to the success of the program are sincerely appreciated. A copy of this letter has also been sent to your co-organizer(s). Please do not hesitate to contact the SRC office by telephone at (301) 634-7010 or via the emails listed below with any questions. We look forward to working with you on this project over the next few years. Sincerely,

Jessica Lyons Conference Manager FASEB Summer Research Conferences jlyons@faseb.org

Emily Benson Conference Manager FASEB Summer Research Conferences ebenson@faseb.org

Robin Crawford Conference Manager FASEB Summer Research Conferences rcrawford@faseb.org

 

2220 Pierce Avenue Phone: 615.936-3582 512-B Preston Building Fax: 615.936-1790   Nashville, TN 37232 scott.hiebert@vanderbilt.edu

Vanderbilt-Ingram Cancer Center

Scott W. Hiebert, Ph.D. Associate Director for Basic Research and Shared Resources

Ingram Professor of Cancer Research Professor of Biochemistry

Dec. 15, 2011 FASEB Summer Research Conference Review Committee Re: Response to queries To the Review Committee: Dr. Ott and I are happy to provide the following responses to the review committee’s queries about our application for a 2013 conference focused on Histone Deacetylases, Sirtuins and Reversible Acetylation in Signaling and Disease:

1) Continuity plan: We agree that a continuity plan is a great idea. Because the history of this meeting is to have 2 new organizers, and because Dr. Ott agreed to serve as co-Chair without a requirement for serving as a Chair of the next meeting, we are proposing the concept of an “Emeritus” Chair, whereby the previous chair would work with the incoming Chair and Co-Chair to ensure a smooth transition and robust fundraising. I would be happy to continue to work with the new Chairs to ensure that the meeting continues to grow.

2) Fundraising: Without question, fundraising is our greatest task as Chair and co-Chair and our goal is to match the efforts of 3 years ago when the meeting was last held in Italy. We recognize that the previous Chairs did not have much success in a very difficult economy raising funds, so we have developed an extensive plan. Our first new avenue for fundraising is tapping into the meeting participants. This meeting has an extremely loyal following and at the end of the last meeting I hatched the idea of asking participants to consider this meeting in their year-end giving. Obviously, we need approval quickly to send emails asking for donations yet this year, but this is the first step. I plan to lay out a challenge of raising $3,000 by the end of this year, by asking the Hdac community to match the Chair’s donation of up to $1,500. We will then use these donations as leverage as we move into the next phase of fundraising. Secondly, we recognize that companies and the NIH budgets are tight. Therefore, we have already started contacting companies to ask for smaller gifts in each of the next 2 years. In addition, we will apply for NIH grants (I believe the previous chair missed the NIH deadline). Thirdly, we believe that private foundations are key to making this a successful meeting. We have already made plans and contacts with various foundations including the Sam Waxman Foundation that is focused on epigenetic research. We also expect to apply to the Leukemia and Lymphoma Society for support as Hdac inhibitors were approved for the treatment of cutaneous T cell lymphoma.

3) Competition from other meetings: While there are other meetings that may overlap with a portion of our meeting (perhaps as much as 20%), there is no other meeting that comes close to the focus of this meeting on HDACs and Sirtuins. This has created a very loyal following and will ensure the continued success of this meeting.

 

2220 Pierce Avenue Phone: 615.936-3582 512-B Preston Building Fax: 615.936-1790   Nashville, TN 37232 scott.hiebert@vanderbilt.edu

Vanderbilt-Ingram Cancer Center

Scott W. Hiebert, Ph.D. Associate Director for Basic Research and Shared Resources

Ingram Professor of Cancer Research Professor of Biochemistry

4) Junior investigators: In each session we have reserved 2 slots for presentations from the poster abstracts. In nearly every case these are filled by junior faculty, postdocs or students and we will ensure that this happens in 2013. We believe that this is an essential component of the meeting that provides links to the future of this research field and provides an important level of excitement for the meeting.

If you have any further questions, please don’t hesitate to contact me. If possible, we would like a response quickly so that we can get a last minute plea for donations to the meeting out before the end of this year. Best Wishes,