Role of cohesin in developmental gene regulation. The major goal of our project is to understand the novel role of cohesin in developmental gene regulation. Cohesin is a conserved and essential multi-protein complex important for sister chromatid cohesion and chromosome segregation during mitosis. Although it was initially identified to be critical for proper segregation of mitotic chromosomes, discoveries of cohesin and cohesin loading factor mutations in the systemic developmental disorder Cornelia de Lange syndrome (CdLS) strongly suggest that cohesin plays an important role in developmental gene regulation. Furthermore, genome-wide analyses of cohesin binding sites revealed an intriguing functional interaction between cohesin and the transcription factor CTCF. Studies of imprinted gene regions suggest that cohesin is an important mediator of the insulator function of CTCF. Since CTCF was shown to mediate chromatin domain interactions, it is possible that cohesin may bring together two distant chromatin regions (perhaps in a manner similar to cohesion of sister chromatids) to influence gene expression. However, this possibility has not been tested. Furthermore, not all cohesin binding sites overlap with those of CTCF, arguing that cohesin may also function in transcriptional regulation independent of CTCF. Our preliminary evidence indicates an active involvement of cohesin in the heterochromatic organization of repeat sequences as well as an activation-induced recruitment of cohesin to a developmentally regulated gene, both of which appear to be independent of CTCF. Thus, the target genes that are directly controlled by cohesin as well as the underlying mechanism of cohesin function in gene regulation remain enigmatic. In this project, we plan to investigate the mechanism and regulation of this novel transcriptional function of cohesin in mammalian cells and to define the important cohesin target genes that are dysregulated in CdLS.
Specific aims are 1) identification of critical target genes that are directly regulated by cohesin using a CdLS mouse model system, and 2) examination of the role of cohesin in chromatin:chromatin interactions affecting transcription in vivo. Characterizing the role of cohesin in transcription is important for understanding the fundamental cellular mechanisms of higher-order chromatin structural organization critical for developmental gene regulation and addressing the pathogenesis of human diseases caused by mutations in cohesin and/or its associated factors.
Cornelia de Lange syndrome (CdLS) is a dominantly-inherited multisystem developmental disorder whose underlying pathogenic mechanism remains unclear. Since most CdLS cases result from mutations of factors related to cohesin, it is essential to understand cohesin's role in this disease's pathogenesis. In the proposed project, we plan to test the hypothesis that the disease is caused by dysregulation of target genes that are directly controlled by cohesin and to address the molecular mechanism of cohesin-mediated gene regulation. The outcome of this study should provide new insight into the molecular events at the root of CdLS, which may lead to the possible development of therapeutic strategies.
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