To develop properly, organisms must not only establish defined patterns of gene expression that specify tissue identity, but also must maintain those gene expression patterns. It is known that one set of mechanisms establishes appropriate expression patterns of master regulatory factors, such as Hox genes, while a second set of mechanisms maintains those expression patterns from early in embryonic development until death of the organism. One family of genes that is required for maintenance, and that functions primarily to maintain genes in a repressed state, is the Polycomb-Group (PcG) of genes. There are at least two major regulatory complexes (PRC and ESC-E(Z) ) that contain PcG genes and that are conserved in function and in core composition from Drosophila to humans. The long terms goal of the studies proposed here is to understand the function of PcG complexes, and to understand the mechanisms that target these complexes to specific Hox genes and cause these complexes to repress Hox expression in a mitotically heritable manner. We propose to characterize the mechanisms that allow PRC to maintain a repressed state and that target PRC action using both Drosophila and human PcG proteins. To test hypotheses for how these complexes function in vivo, we propose to characterize the chromatin of the human Hox clusters, and to develop in vitro systems to directly analyze the function of PRC (and other PcG complexes) on important regulatory sites within the Hox clusters. These studies will begin to address how these key regulatory complexes function to create an accurately maintained state of Hox gene repression.
The Aims are: 1) Targeting of PRC complexes; 2) Characterization of a PRC repressed template; 3) Characterization of mammalian Hox clusters in vivo; 4) Detailed analysis of regulation of Hox gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043901-15
Application #
6897189
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Carter, Anthony D
Project Start
1991-05-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
15
Fiscal Year
2005
Total Cost
$614,821
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Ardehali, M Behfar; Anselmo, Anthony; Cochrane, Jesse C et al. (2017) Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription. Mol Cell 68:872-884.e6
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Mueller, Britta; Mieczkowski, Jakub; Kundu, Sharmistha et al. (2017) Widespread changes in nucleosome accessibility without changes in nucleosome occupancy during a rapid transcriptional induction. Genes Dev 31:451-462
Tchasovnikarova, Iva A; Timms, Richard T; Douse, Christopher H et al. (2017) Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nat Genet 49:1035-1044
Lau, Mei Sheng; Schwartz, Matthew G; Kundu, Sharmistha et al. (2017) Mutation of a nucleosome compaction region disrupts Polycomb-mediated axial patterning. Science 355:1081-1084
Kundu, Sharmistha; Ji, Fei; Sunwoo, Hongjae et al. (2017) Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation. Mol Cell 65:432-446.e5
Deaton, Aimee M; Gómez-Rodríguez, Mariluz; Mieczkowski, Jakub et al. (2016) Enhancer regions show high histone H3.3 turnover that changes during differentiation. Elife 5:
Yildirim, Ozlem; Kingston, Robert E (2016) Molecular Dissection of Chromatin Maturation via Click Chemistry. Curr Protoc Mol Biol 114:21.33.1-21.33.11

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