Histone Methylation Marks : Permanent or Reversible?

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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: 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

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

Difference between Histone Methylation and Acetylation MethylationAcetylation Modifica tion Site Lysine and Arginine Lysine StabilityGenerally reversible Generally stable FunctionTranscriptional Activation OR Repression Generally Transcriptional Activation

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

Inheritable Methylation Marks Cell 125, April 21, 2006

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

Mechanism of Gene Silencing Mediated by Histone Methylation

Events Against the “Stable” Nature of Histone Methylation Cyclin E Promoter Yeast Promoter Active Inactive G1 S Inactivated Activated H3K9 MethylationH3K9 Demethylation? H3K4 TrimethylationH3K4 Dimethylation

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

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

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

LSD-1 is Evolutionarily Conserved

LSD-1 Is a Transcriptional Repressor

Demethylation of diMeK4H3 Peptides by LSD1

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

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

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

Conclusion LSD1 represses Gene Transcription via Directly Demethylating Histone DimeH3K4

Other Methyl Marks found to be Demethylated JMJD3: Demethylate TriMeH3K27 Mouse Neural Stem Cells: RA JMJD3 Differentiation(Nature,Vol 450(15) November 2007) RAW264.7 Macrophage: LPS NF-kappa B JMJD3 macrophage plasticity (Cell 130, 1083–1094, September 21, 2007)

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

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