Abstract

Gene expression in eukaryotes is modulated by positional information and higher order repressive chromatin structure (heterochromatin). Chromatin remodeling complexes have been implicated in the disruption of such repressive chromatin resulting in modulation of transcription, DNA replication, and DNA repair. Mutations in the components of these chromatin modifying complexes leads to severe developmental defects (e.g. ATRx, MeCP2) and cancer development (e.g. SNF5, CBP). We are focused on chromatin remodeling complexes containing the human chromatin-remodeling factor Imitation Switch (ISWI) protein.We hypothesize that ISWI-containing complexes facilitate gene expression by altering the structure of a higher order chromatin structure, known as heterochromatin. The three Aims are designed to provide a thorough biochemical and functional characterization of human ISWI-containing complexes.
Aim 1 will identify the remaining subunits of the 1-1.5 MDa ISWI/WSTF- containing complex and describe experiments that will begin to define the chromatin remodeling activity of the complex and the individual proteins in the complex.
Aim 2 describes a detailed functional analysis of human ISWI-complexes with emphasis on their putative role in heterochromatin modulation.
Aim 3 extends the work to tissue-specific chromatin remodeling complexes containing human SNF2L and use a cell line expressing FLAG-tagged SNF2L protein to identify and functionally characterize the SNF2L chromatin remodeling complex.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061204-03
Application #
6628920
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Carter, Anthony D
Project Start
2001-02-01
Project End
2006-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
3
Fiscal Year
2003
Total Cost
$283,327
Indirect Cost

  Institution

Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Smith, Edwin R; Lee, Min Gyu; Winter, Benjamin et al. (2008) Drosophila UTX is a histone H3 Lys27 demethylase that colocalizes with the elongating form of RNA polymerase II. Mol Cell Biol 28:1041-6
Eissenberg, Joel C; Lee, Min Gyu; Schneider, Jessica et al. (2007) The trithorax-group gene in Drosophila little imaginal discs encodes a trimethylated histone H3 Lys4 demethylase. Nat Struct Mol Biol 14:344-6
Nicolas, Estelle; Lee, Min Gyu; Hakimi, Mohamed-Ali et al. (2006) Fission yeast homologs of human histone H3 lysine 4 demethylase regulate a common set of genes with diverse functions. J Biol Chem 281:35983-8
Lee, Min Gyu; Wynder, Christopher; Norman, Jessica et al. (2006) Isolation and characterization of histone H3 lysine 4 demethylase-containing complexes. Methods 40:327-30
Lee, Min Gyu; Wynder, Christopher; Bochar, Daniel A et al. (2006) Functional interplay between histone demethylase and deacetylase enzymes. Mol Cell Biol 26:6395-402
Lee, Min Gyu; Wynder, Christopher; Schmidt, Dawn M et al. (2006) Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem Biol 13:563-7
Wynder, Christopher; Hakimi, Mohamed-Ali; Epstein, Jonathan A et al. (2005) Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation. Nat Cell Biol 7:1113-7
Zhou, Jing; Chau, Charles M; Deng, Zhong et al. (2005) Cell cycle regulation of chromatin at an origin of DNA replication. EMBO J 24:1406-17
Banting, Graham S; Barak, Orr; Ames, Tanya M et al. (2005) CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L. Hum Mol Genet 14:513-24
Barak, Orr; Lazzaro, Maribeth A; Cooch, Neil S et al. (2004) A tissue-specific, naturally occurring human SNF2L variant inactivates chromatin remodeling. J Biol Chem 279:45130-8

Showing the most recent 10 out of 13 publications