The long-term goal of the proposed work is to determine how sister chromatid cohesion proteins participate in the control of gene transcription. The results will illuminate mechanisms that underlie human genetic syndromes and cancers. The cohesin protein complex holds sister chromatids together until a cell divides, thereby ensuring accurate chromosome segregation. Moderate reductions in cohesin activity do not affect chromosome segregation. Instead, they alter transcription of many genes, leading to poor growth and development in organisms from Drosophila to humans. High cohesin levels are linked to poor prognosis in breast and endometrial cancers, which likely reflects cohesin's roles in facilitating transcription of genes that promote cell proliferation. Studies over the past fiften years show that cohesin helps enhancers stimulate transcription of genes located many kilobases away. Recent data reveal that cohesin binds all enhancers, and thousands of gene promoters. These data unexpectedly also show that cohesin levels are higher at enhancers than at promoters, and predict that cohesin binding is stable at enhancers, but unstable at promoters. These and other findings argue against the prevailing concept that cohesin holds enhancers and promoters together by a chromatid cohesion-related mechanism, which would require stable cohesin at promoters. The proposed work tests the new model that dynamic cohesin turnover at promoters facilitates binding of RNA polymerase, and prevents sister chromatid cohesion, which would inhibit enhancer-promoter looping. In this model, cohesin at promoters interacts with other transcriptional regulators, such as the Mediator complex, to facilitate enhancer-promoter looping. These and related ideas will be tested in vivo and in vitro, using genomic, biophysical, biochemical, and genetic approaches. The proposed studies will more clearly delineate the mechanisms by which cohesin facilitates enhancer- promoter communication, and potentially suggest new methods for correcting defects caused by moderate changes in cohesin activity in genetic syndromes and cancer.
This project is to determine how proteins that control the proper division of chromosomes when cells divide also control genes, development, and tumor growth. Reductions in these proteins cause Cornelia de Lange syndrome (CdLS), a severe developmental disorder and increases are associated with poor cancer prognosis. By examining how these proteins work, we will gain knowledge that will aid the search for new methods to diagnose and treat CdLS patients and certain cancers.
| Misulovin, Ziva; Pherson, Michelle; Gause, Maria et al. (2018) Brca2, Pds5 and Wapl differentially control cohesin chromosome association and function. PLoS Genet 14:e1007225 |
| Rickels, Ryan; Herz, Hans-Martin; Sze, Christie C et al. (2017) Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nat Genet 49:1647-1653 |
| Swain, Amanda; Misulovin, Ziva; Pherson, Michelle et al. (2016) Drosophila TDP-43 RNA-Binding Protein Facilitates Association of Sister Chromatid Cohesion Proteins with Genes, Enhancers and Polycomb Response Elements. PLoS Genet 12:e1006331 |
| Dorsett, Dale (2016) The Drosophila melanogaster model for Cornelia de Lange syndrome: Implications for etiology and therapeutics. Am J Med Genet C Semin Med Genet 172:129-37 |
