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Cavalli lab - Polycomb Epigenetics - Current Research
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DNA is folded into chromatin in the cell nucleus, and chromatin is an essential component in the regulation of genome function. Chromatin factors are thus regulating most gene regulatory processes, in particular those that take place during development. A key feature of development in metameric animals is the definition of body segments where groups of cells with a specified fate will give rise to their relative body structures. Cell fates are specified by particular combinations of homeotic gene products. During early embryogenesis, maternal and segmentation genes regulate homeotic genes by binding to specific regulatory sequences located in the promoter regions.  Later in development, the expression pattern of homeotic genes as well as other important developmental genes are maintained by a cell memory system dependent on two groups of genes. The members of these two groups are epigenetic regulators able to recognize the active and inactive state of expression and fix it to the cell progeny through many cell divisions. These components have been classically assigned to  two genetic groups. The trithorax-group (trxG) can maintain the active state of expression, while the Polycomb-group (PcG) counteracts this activation with a stable repressive function

 

The mechanisms used to recruit the appropriate regulatory complex to its gene targets in each cell type are still debated. The first model was proposing that sequence-specific DNA binding proteins bind at so-called Polycomb response elements (PREs). These proteins might recruit the PcG complex called PRC2, which trimethylates histone H3 lysine 27 (H3K27me3). H3K27me3 might then be recognized by the chromo domain of the PC subunits of PRC1. More recent work has shown, however, that non canonical PRC1 complexes may in turn stabilize recruitment of PRC2. Once recruited, PcG complexes can propagate silencing through cell division. 

 

In addition to the transmission of cellular memory, PcG proteins may also regulate dynamic processes. Genome-wide mapping studies have shown that PcG target genes encode for components controlling major signalling pathways and, importantly, PcG misexpression has also been associated with many cancer types, including breast and prostate cancer. In mammalian embryonic stem cells, many PcG target genes have been reported to bear both repression- and activation-associated marks. Upon differentiation, these “bivalent states” are resolved into fully active or fully repressed. In some instances, PcG components may even activate transcription, although it is unclear whether this phenomenon is widespread or rare. Importantly, we and others have shown that PcG proteins regulate the organization of their target genes in the three-dimensional space of the nucleus, and this regulatory function is involved in the maintenance of cellular memory.

 

We would like to understand the molecular mechanisms of action of these factors, the role of regulation of higher order chromatin structure and nuclear organization in gene regulation, and the key molecular pathways that are mobilized by these proteins to coordinate the regulation of cell differentiation with that of cell proliferation. In particular, our research aims at (1) understanding, on a genome-wide scale, how these proteins are targeted to DNA and what are the consequences of this targeting on chromatin structure (2) understanding the effect of PcG proteins on cell proliferation, cell differentiation and cell polarity, and to dissecting the key components regulated by PcG proteins to modulate these pathways in specific tissues and developmental processes; (3) identifying the rules governing the distribution of their target genes in the cell nucleus and the effect of this organization on gene expression; (4) understanding the phenomenon of transgenerational epigenetic inheritance, namely how widespread it is, what are the components that regulate it and the molecular mechanisms that are at play.


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Last update: 06/01/2015