Elucidation of the molecular mechanisms involved in the epigenetic regulation of gene expression remains the 'holy grail' for many research fields in biology. Recently, we made the exciting discovery of the first bona fide histone demethylase. The identification of Lysine-Specific Demethylase 1(LSD1), an H3-lysine 4 (H3- K4) specific histone demethylase confirmed the long held speculation regarding the reversible nature of histone methylation, and represents a major advance in our understanding of epigenetic regulation. LSD1 functions as an FAD dependent transcriptional corepressor and is found in a variety of multi-subunit complexes. A detailed knowledge of the precise mechanisms underlying the activity and regulation of these chromatin modulating complexes and their components is an essential step toward the eventual understanding of the essence of both genome organization and genomic information processing. The focus of our research is on the regulation of histone demethylases and the biological consequences of histone demethylation in gene regulation and DNA repair, which are two of the most essential events during stem cell differentiation, embryonic development, and cancer progression. Furthermore, we intend to identify additional novel histone demethylases, including those that may either exhibit alternative substrate specificities and perhaps different chemical mechanisms. These data will contribute further to this quickly moving and groundbreaking field of epigenetics. The findings from the studies described here will provide specific insights into the mechanisms underlying histone demethylation and will expand our knowledge of general epigenetic regulation as it relates to nearly every facet of genome-related biology and rapidly emerging cancer epigenetics. This work will undoubtedly have significant impact on a variety of human pathologies, including tumorigenesis and developmental anomalies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078458-02
Application #
7268786
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Carter, Anthony D
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$325,363
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Larson, Allison R; Dresser, Karen A; Zhan, Qian et al. (2014) Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors. Mod Pathol 27:936-44
Chen, Fei; Yang, Huirong; Dong, Zhenghong et al. (2013) Structural insight into substrate recognition by histone demethylase LSD2/KDM1b. Cell Res 23:306-9
Tan, Li; Xiong, Lijun; Xu, Wenqi et al. (2013) Genome-wide comparison of DNA hydroxymethylation in mouse embryonic stem cells and neural progenitor cells by a new comparative hMeDIP-seq method. Nucleic Acids Res 41:e84
Fang, Rui; Chen, Fei; Dong, Zhenghong et al. (2013) LSD2/KDM1B and its cofactor NPAC/GLYR1 endow a structural and molecular model for regulation of H3K4 demethylation. Mol Cell 49:558-70
Lian, Christine Guo; Xu, Yufei; Ceol, Craig et al. (2012) Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150:1135-46
Xu, Yufei; Xu, Chao; Kato, Akiko et al. (2012) Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 151:1200-13
Gu, Tian-Peng; Guo, Fan; Yang, Hui et al. (2011) The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477:606-10
Xu, Yufei; Wu, Feizhen; Tan, Li et al. (2011) Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 42:451-64
Pojoga, Luminita H; Williams, Jonathan S; Yao, Tham M et al. (2011) Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension. Am J Physiol Heart Circ Physiol 301:H1862-71
Zhang, Haikuo; Zhang, Xin; Clark, Erin et al. (2010) TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. Cell Res 20:1390-3

Showing the most recent 10 out of 11 publications