The systematic study on the epigenomics of mei-Cohesins in the norm and as Cancer-Testis proteins

Abstract

Meiotic cohesin subunits are frequently expressed in cancers as Cancer-Testis (CT) Genes, and are potentially linked to the onset and proliferation of tumor cells. However, the roles of CT genes, and mei-Cohesin components in particular, in cancer were not studied in depth. In order to address this gap in research we took two approaches : the epigenomics of mei-Cohesin in normal primate testis and the reconstitution of mei-Cohesin complexes in somatic cell lines, both normal and transformed. Applying a novel ChIP-ChEP-seq method in Macaca fascicularis testis, we elucidated the overlapping pattern of mei-Cohesin binding to germline chromosome arms and centromeric repeats for SMC1b, STAG3, RAD21L and REC8 subunits. We also uncovered the rules guiding the cohabitation of mei-Cohesins with BORIS/CTCFL and CTCF-containing regulatory sites controlling gene expression and 3D chromatin structure during the spermatogenesis. Finally, by reconstituting REC8 and RAD21L based mei-Cohesin complexes in human somatic cell lines, we discovered the governing principles for mei-Cohesin binding to chromatin. The introduction of particular combinations of mei-Cohesin subunits into such a system was setting up a potential competition with somatic cohesin complex based on RAD21, resulting in chromosome instability phenotype. As a result of this work, we elucidated the potential biological roles of mei-Cohesin expressed as CT genes in cancer cells.