CTCF and CTCF and Imprinting Imprinting DisorderDisorder
Preeti MisraSang-Gook
Han
Contents
•Gene Network
•Epigenetic - Acetylation - Methylation
•Properties of CTCF
•Pathway - CTCF
•Human diseases
Background Interesting Protein and Diseases
•Loss of Imprinting
Background: Gene Network
• Activation and Inhibition with evolution
Control: Achieve an objective of the system
Survival, reproduction
P(t)
H(t)
+U(t) Y(t)
-
+C(t)
Background: EpigeneticEpigenetic : Surface of genetic Gene expression control without modification of
DNA sequence.
Histone Modification–Acetylation–Methylation
DNA Methylation - Methylation of Cystosine(C). - CpG island
Expansion Condensation
Background: Epigenetic
DNA Methylation
• Post-synthetic modifications of Chromatin structure
• Cytosine-Guanine (CG) base pair is methylated.
• Regulation in gene expression.
Background: Loss of epigenetic marks.
Background: Genomic Imprinting
DMR: Differentially Methylated RegionICR: Imprinting Control Region
father
mother
CTCF Protein
• Gene location: 16q22• 11 zinc fingers.• Transcription Binding Factor : (MYC, PLK, PIM-1, p19ARF, and
Igf2/H19, APPβ,β-globin, and lysozyme regulatory sequences )
• Binding to TFBSs including ICR and CpG island.• Cis-regulartory.• Regulation of DNA methylation pattern• Highly conserved.• There are 39,622 ZnFg registered in pFam
CTCF motif
CTCF Structure Classification and GO
C - x(2,4) - C - x(3) - [LIVMFYWC] - x(8) - H - x(3,5) – HGSSGSSGRTHTGEKPYACSHCDKTFRQKQLLDMHFKRYHDPNFVPAAFVCSKCGKTFTRRNTMARHADNCAGPDGVEGENSGPSSG
CTCF Protein : C2H2 type
CTCF and its Uses
• CTCF is involved in the control of cell growth and differentiation. • Involved in IGF2 imprinting regulation.
• CTCF may represent a novel tumor suppressor gene that displays tumor-specific "change of function" rather than complete "loss of function“.
• CTCF may establishes a regulatable epigenetic switch for X-inactivation
Human Disease: Beckwith-Wiedemann
syndromeBWS locus: 11p15.5
BWS occurs in 1:13,700
Phenotypes:
1. Macroglossia:
Problem with Eating, Breathing, speaking
2. Abdominal wall defects
3. Fast growth:
birth weight and height (above mean)
enlarge internal organs (kidneys, liver,pancreas)
hemihyperplasia
4. Ear lobe
Pathway : BWS
CTCF Inhibit the enhancer from activating IGF2(Insulin-like Growth Factor 2) and causes H19 to be expressed.
Wilms’ Tumor BWS Tumor
Mutation
ZF3 ZF3 ZF3 ZF7
Other Diseases • Prader-Willis Syndrome(PWS)-failure to thrive during infancy and hyperphagia.
• Angelman syndrome(AS)- mental retardation and speech impairment
• Transient neonatal diabetes mellitis(TNDM)-a rare form of
diabetes
• Alpha-thalassemiaoccurs(males)- mental retardation syndrome.
Capta
Capta
Catpa
Reference• http://www.benbest.com/health/cancer.html
• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=10664
• Marcus Vinicius de Matos Gomes; Ester Silveira Ramos (2003), Beckwith-Wiedemann syndrome and isolated hemihyperplasia, Sao Paulo Med J. 21, 133-138
• Keith D. Robertson (2004), DNA Methylation and Human Disease, Nature, 6, 597-610
• Galina N. Filippova, et. al. (2002), Tumor-associated Zinc Finger Mutations in the CTCF Transcription Factor Selectively Alter Its DNA-binding Specificity, Cancer Research, 62, 48-52
Question Time!!!!