CHROMATIN RE-MODELLING

Presented by:Roll no. 10 : PragyeshDhungel Roll no.21 : Nirjal MainaliRoll no. 34 : Sunil Timilsena

Introduction Gene Expression in Eukaryotes may

include Chromatin Remodelling as part of transcriptional activation.

Chromatin remodeling is the enzyme-assisted movement of nucleosomes on DNA.

Basic subunit of chromatin. i.e Nucleosome

Eukaryotic DNA is tightly packaged into repeated structures known as nucleosomes.

 Individual nucleosomes consist of histone octamers with 146 (or 147) base pairs of double-helix DNA wrapped around it.

Histone Protein can physically block interaction between Promoter DNA sequences and protein needed to initiate transcription.

Chromatin rearrangement modifies the Histone-DNA structure so that transcription can occur.

Basic Technique1. Remodeling: change in nucleosome

structure, but no change in position2. Sliding: displacing nucleosome along

DNA3. Transfer: removing and transferring

nucleosome to non-adjacent region of DNA

Two classes of chromatin remodeling enzymes

Two classes of enzymes that regulate chromatin structure are:

a) Class I : Histone acetylase

b) Class II : Chromatin remodeling factors

Class I : Histone acetylase Don’t alter nucleosome position Covalent modification of histone proteins. Includes histone tail modifications (Ac,

Me, P, Ub, etc.) Proteins recruited by these modifications

include: i)transcription factors ii)ATP-dependent nucleosomal remodeling enzymes iii)histone modifying enzymes

Regulation of histone acetylation in yeast

Class II : Chromatin remodeling factors

It shifts nucleosome position with respect to DNA, exposing regulatory sequences.

These are often refered to as Swi/Snf factors because they were first identified as yeast mutants defective in mating type switching and in the ability to metabolize sucrose (sucrose non-fermenting).

Chromatin remodeling is an active process Chromatin remodeling factors use energy from ATP

hydrolysis to rearrange the packing of nucleosomes in higher order chromatin structures.

Remodeling improves access to DNA or histone binding sites recognized by transcriptional regulators or histone modifiers.

Some of these bind to :i) Activation domains and de-condense the associated chromatin.ii) Repression domains and condense the associated chromatin.

heterochromatin(condensedChromatin)

Euchromatin(De-condensedChromatin)

Classifying Chromatin Remodelers Chromatin remodeling complexes are

classified based on protein motifs found in addition to the ATPase domain, or on how the ATPase domain itself is structured.

This classification is purely structural, designed to make it easier for us humans to sort them all out – it may not accord with functional criteria.

SWI2/SNF2 ATPase

SUPERFAMILY

SWI2/SNF2subfamily

ISWIsubfamily

CHD/Mi2subfamily

Ino80subfamily

ATPase BROMO

ATPase SANT

ATPase

DNA bindingCHROMO

ATPase ATPase

Shared characteristics of chromatin remodeling Complexes :

• Bind nucleosomes

• Are DNA-dependent ATPases

• Recognize histone modifications

• ATPase activity can be regulated

• Interact with other proteins

Role In Transcription:eg. Nucleosome remodeling in yeast

SWI/SNFcomplex

SAGAcomplex

DHS

Chromatin and cancer: Cancer can occur when essential

regulatory proteins are altered such that development stops but the cells can still divide.

Examples: avian Erythroblast virus changing normal functional properties of thyroid hormone receptor(TR) by introducing oncoprotein v-ErbA.

Acute myeloid leukemia(AML) and Promyelocytic leukemia(PML) in humans

Oncoprotein v-ErbA: TR directs differentiation of chicken blood

cells by binding to thyroid hormone, through targeting of chromatin remodeling machinery including histone transferases.

but v-ErbA, cant bind to thyroid hormone, so can't recruit histone transferases,

instead recruits histone deacetylase to block specialized cell funtions,

causing proliferation of cells leading to leukemia.

AML and PML: associated with chromosomal

translocations. In AML, gene that is disrupted encodes a

transcription factor AML-1, which controls myeloid specific gene expression.

in chromosomal translocation, DNA binding domain of AML-1 binds with a protein

ETO, that interacts with a histone deacetylase, that leads to repression of cell differentiation and leads to leukemia.

Similarly in PML, retonic acid receptor(RAR) (recruits histone deacetylase) binds to PML and leads to to failure of myelocytes to differentiate and results leukemia.

PML-RAR can bind with trans-retonoic acid which leads to conformational change to PML-RAR and release of histone deacetylase.

This leads to remission of leukemia.

in cell cycle controlling pathways also mutated genes like

cyclin dependent kinase inhibitors(p16) and retinoblastoma(Rb)

cause cancer. but if recognition and selective inhibition of

these chromatin remodelling pathways can be done then cancer can be

cured. thus this area has a wide scope in therapeutic

and pharmaceutical industry.

References http://www.nature.com/onc/journal/v20/n

24/full/1204322a.html http://highered.mcgrawhill.com/sites/983

4092339/student_view0/chapter10/chromatin_remodeling.html

http://www.sabiosciences.com/pathway.php?sn=Chromatin_Remodeling

http://www.sigmaaldrich.com/life-science/your-favorite-gene-search/pathway-overviews/chromatin-remodeling.html