histone methylation marks : permanent or reversible?
DESCRIPTION
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: - PowerPoint PPT PresentationTRANSCRIPT
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”