Transcription is temporally and spatially regulated via changes in chromatin structure. Gene regulation via formation of transcriptionally active or inactive chromatin is stable' d to be a cellular memory system that is responsible for the inheritance of gene activity to progeny cells. In quiescent cells, these mechanisms appear to be involved in stable long-term repression of a variety of genes, which are responsible for cell proliferation. Indeed, such sealing of """"""""unnecessary"""""""" genes is crucial for maintaining the quiescent state. Accordingly, any defect in such silencing mechanisms results in the expression of """"""""unnecessary"""""""" genes in quiescent cells, leading to tumorigenesis. While many factors that are responsible for silencing have been identified by genetic screening, mechanisms by which they contribute to the formation of inactive chromatin remain largely unclear. To explore these mechanisms, we have purified a key protein complex that plays important roles in the formation of inactive chromatin in quiescent cells. Further characterization of this complex will provide new insights into mechanisms by which normal cells maintain the quiescent state, and further, by which transcription is perturbed in tumor cells. ? ? Moreover, we will investigate how the patterns of transcriptional activity are transmitted to progeny cells. Several lines of evidence suggest that histone H2AZ, a major histone variant that occupies 5% to 10% of total H2A, is deposited onto transcriptionally active chromatin. To reveal mechanisms by which histone H2AZ is incorporated into active chromatin and contribute to gene activation, we have purified at least two H2AZ-containing complexes. Functional analyses of these complexes will solve, at least in part, the puzzle of how histone H2AZ exerts its specific and diverse effects to transmit the patterns of transcriptionally active chromatin to progeny cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065939-03
Application #
6760038
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Carter, Anthony D
Project Start
2002-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$359,100
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Nakatani, Y; Tagami, H; Shestakova, E (2006) How is epigenetic information on chromatin inherited after DNA replication? Ernst Schering Res Found Workshop :89-96
Tagami, Hideaki; Ray-Gallet, Dominique; Almouzni, Genevieve et al. (2004) Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116:51-61
Nakatani, Y; Ray-Gallet, D; Quivy, J-P et al. (2004) Two distinct nucleosome assembly pathways: dependent or independent of DNA synthesis promoted by histone H3.1 and H3.3 complexes. Cold Spring Harb Symp Quant Biol 69:273-80
Quivy, Jean-Pierre; Roche, Daniele; Kirschner, Doris et al. (2004) A CAF-1 dependent pool of HP1 during heterochromatin duplication. EMBO J 23:3516-26