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.
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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 |
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| West, Jason A; Mito, Mari; Kurosaka, Satoshi et al. (2016) Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization. J Cell Biol 214:817-30 |
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