Covalent modifications (phosphorylation, acetylation, ubiquitination and methylation) of histone N-terminal tails significantly impact chromatin structure and gene transcription. While many of these modifications are regulated dynamically by enzymes of opposing activities, histone methylation has long been considered a """"""""permanent"""""""" modification. We have recently discovered the first histone demethylase LSD1 (Lysine Specific Demethylase 1), which represses transcription by demethylating histone H3 lysine 4 (H3-K4), demonstrating that histone methylation, like other histone modifications, is also regulated dynamically. Our findings raise a number of important and exciting questions. For instance, how is LSD1-mediated demethylation regulated? What are the biological functions of LSD1? Our preliminary findings suggest a potentially very exciting role for BHC80, an LSD1 associated factor, in regulating chromatin events post H3-K4 demethylation mediated by LSD1, and a possible connection to lipid signaling. Investigation of mechanisms by which BHC80 regulates LSD1 is a focus of this application. To understand the biology and in vivo mechanism of action of histone demethylases, we will analyze the roles of S. pombe LSD1 homologs, SPBC146.09C and SPAC23E2.02, in both euchromatin and heterochromatin biology. Pombe heterochromatin is characterized by H3-K9 methylation and H3-K4 hypomethylation, which is consistent with a possible role for LSD1 homologs in heterochromatin. Epigenetic regulation of gene expression via histone modifications has been linked to multiple pathological conditions including cancer. Thus, an understanding of demethylases in heterochromatin as well as euchromatin gene transcription will provide new insights not only into chromatin biology but also cell proliferation control and tumorigenesis in general. Based on our exciting initial results, the proposed studies are likely to result in new paradigms that will significantly impact our views of eukaryotic chromatin and transcriptional regulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118487-05
Application #
7826952
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Okano, Paul
Project Start
2006-07-13
Project End
2010-06-30
Budget Start
2010-06-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$145,803
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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