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Histone Methylation Marks : Permanent or Reversible?

Histone Methylation Marks : Permanent or Reversible?. Epigenetics Background. Study of heritable changes in gene expression that are not due to changes in DNA sequence DNA methylation Histone Code Chromatin Remodeling. Histone Code. Implications:

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Histone Methylation Marks : Permanent or Reversible?

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  1. Histone Methylation Marks: Permanent or Reversible?

  2. Epigenetics Background • Study of heritable changes in gene expression that are not due to changes in DNA sequence • DNA methylation • Histone Code • Chromatin Remodeling

  3. Histone Code Implications: 1. Combination of differentially modified neucleomes higher order chromatin 2. Different modifications interact with each other, either synergistic or antagonistic 10 AUGUST 2001 VOL 293 SCIENCE

  4. Methylation Sites and Chemical Structures Cell, Vol. 109, 801–806, June 28, 2002

  5. Difference between Histone Methylation and Acetylation

  6. Methylation Marks-Dynamic or Static? • Considerably lower turnover than phosphorylation and acetylation • The same turnover as Histone • No HDMase identified then • Stable “Methylation Marks”

  7. Inheritable Methylation Marks Cell 125, April 21, 2006

  8. Biological Role of Methylation Marks • Oncogenesis(Activating Oncogene Transcription) • H3K4me2 • Long-term silencing Hox gene: H3K9me2, H3k27me3 • Inactivating X chromosome in female mammals:H3k27me3, H3K9me2, H4K20me1 • Maintaining ES cell pluripotency and plasticity: H3k27me3

  9. Mechanism of Gene Silencing Mediated by Histone Methylation

  10. Events Against the “Stable” Nature of Histone Methylation • Cyclin E Promoter • Yeast Promoter Active Inactive G1 S Inactivated Activated H3K9 Methylation H3K9 Demethylation? H3K4 Trimethylation H3K4 Dimethylation

  11. How can Methylation Marks be Removed? Cell, Vol. 109, 801–806, June 28, 2002

  12. Groundbreaking Experiment: Identification of the First Histone Demethylase • First enzyme responsible for histone lysine demethylation • LSD1 DiMeH3K4 Cell, Vol. 119, 941–953, December 29, 2004

  13. Hints: • KIAA0601(LSD1) involved in various corepressor complex • SPR-5 (C. elegans homolog) involved in transcriptional repression • Target: try to find out whatKIAA0601 do and how it works

  14. LSD-1 is Evolutionarily Conserved

  15. LSD-1 Is a Transcriptional Repressor

  16. Demethylation of diMeK4H3 Peptides by LSD1

  17. Specific Demethylation at K4 of Histone H3 by LSD1 but Not LSD1C

  18. LSD1 Converts diMeK4H3 Peptides to Peptides with Molecular Weight Corresponding to Unmodified H3

  19. LSD1 Regulation of Endogenous Target Gene Transcription and H3-K4 Methylation In Vivo

  20. Conclusion • LSD1 represses Gene Transcription via Directly Demethylating Histone DimeH3K4

  21. Other Methyl Marks found to be Demethylated • JMJD3: Demethylate TriMeH3K27 • Mouse Neural Stem Cells: RA JMJD3 Differentiation(Nature,Vol450(15)November 2007) RAW264.7 Macrophage: LPS NF-kappa B JMJD3 macrophage plasticity (Cell 130, 1083–1094, September 21, 2007)

  22. Currently Identified Histone Demethylase JMJD3,UTX Cell 125, April 21, 2006

  23. Perspective • Characterization of More Demethylases and Their Biological Roles • Reveal More Key Regulatory Processes Dependent on Reversal of “Stable Methylation Marks”

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