Histone Methylation Marks: Permanent or Revers

ible?

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

Methylation AcetylationModification Site

Lysine and Arginine

Lysine

Stability Generally reversible

Generally stable

Function Transcriptional 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 Methylation H3K9 Demethylation?

H3K4 Trimethylation H3K4 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 Methylatio

n 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”