1. CTCF and Imprinting Disorder Preeti Misra Sang-Gook Han

2. Contents Gene Network Epigenetic - Acetylation - Methylation Properties of CTCF Pathway - CTCF Human diseases Background Interesting Protein and Diseases Loss of Imprinting

3. 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)

4. Background: Epigenetic Epigenetic : Surface of genetic Gene expression control without modification of DNA sequence. Histone Modification –Acetylation –Methylation DNA Methylation - Methylation of Cystosine(C). - CpG island ExpansionCondensation

5. Background: Epigenetic

6. DNA Methylation Post-synthetic modifications of Chromatin structure Cytosine-Guanine (CG) base pair is methylated. Regulation in gene expression.

7. Background: Loss of epigenetic marks.

8. Background: Genomic Imprinting DMR: Differentially Methylated Region ICR: Imprinting Control Region father mother

9. 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

10. CTCF motif

11. CTCF Structure Classification and GO

12. C - x(2,4) - C - x(3) - [LIVMFYWC] - x(8) - H - x(3,5) – H GSSGSSGRTHTGEKPYACSHCDKTFRQKQLLDMHFKRYHDPNFVPAAFVCS KCGKTFTRRNTMARHADNCAGPDGVEGENSGPSSG CTCF Protein : C2H2 type

13. 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

14. Human Disease: Beckwith-Wiedemann syndrome BWS 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

15. Pathway : BWS CTCF Inhibit the enhancer from activating IGF2(Insulin-like Growth Factor 2) and causes H19 to be expressed. Wilms’ Tumor BWS Tumor

16. Mutation ZF3 ZF7

17. 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.

18. Capta

20. Catpa

21. Reference http://www.benbest.com/health/cancer.html http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Gr aphics&list_uids=10664http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Gr aphics&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

22. Question Time!!!!