Regulation of the Drosophila Enhancer of split and invected-engrailed Gene Complexes by Sister Chromatid Cohesion Proteins

Abstract

The cohesin protein complex was first recognized for holding sister chromatids together and ensuring proper chromosome segregation. Cohesin also regulates gene expression, but the mechanisms are unknown. Cohesin associates preferentially with active genes, and is generally absent from regions in which histone H3 is methylated by the Enhancer of zeste [E(z)] Polycomb group silencing protein. Here we show that transcription is hypersensitive to cohesin levels in two exceptional cases where cohesin and the E(z)-mediated histone methylation simultaneously coat the entire Enhancer of split and invected-engrailed gene complexes in cells derived from Drosophila central nervous system. These gene complexes are modestly transcribed, and produce seven of the twelve transcripts that increase the most with cohesin knockdown genome-wide. Cohesin mutations alter eye development in the same manner as increased Enhancer of split activity, suggesting that similar regulation occurs in vivo. We propose that cohesin helps restrain transcription of these gene complexes, and that deregulation of similarly cohesin-hypersensitive genes may underlie developmental deficits in Cornelia de Lange syndrome.

Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments

“…Importantly, the homogenization of interactions that results from this shift is consistent with the pattern of deregulated gene expression in cohesin-deficient thymocytes. Similar to previous observations in Drosophila (Schaaf et al 2009), genes at the low end of the expression spectrum were preferentially up-regulated, whereas genes at the high end of the expression spectrum were preferentially down-regulated. Perhaps this is the genome-scale equivalent of the ability of CTCF and CTCF-associated cohesin to mediate insulator and boundary functions.…”

Wapl antagonizes cohesin binding and promotes Polycomb-group silencing inDrosophila

“…In the rare cases where cohesin binding overlaps H3K27me3, the genes are Fig. 6. pds5 enhances and Nipped-B not fully silenced (Schaaf et al, 2009). Although this is consistent with the idea that cohesin counteracts silencing, in fact cohesin negatively regulates expression in these unusual cases, in part by blocking transition of paused RNA polymerase to elongation (Fay et al, 2011).…”

Cohesin loading and sliding

“…A recent comprehensive analysis of the consequences of cohesin disruption on gene expression from polytene chromosomes in Drosophila salivary gland cells has revealed a role for cohesin in both the upregulation and downregulation of several genes in the vicinity of its binding sites (Pauli et al, 2010). How cohesin and changes to its expression levels result in distinct transcriptional outcomes at individual gene loci and in different cell types is incompletely understood (Schaaf et al, 2009).…”

“…A recent comprehensive analysis of the consequences of cohesin disruption on gene expression from polytene chromosomes in Drosophila salivary gland cells has revealed a role for cohesin in both the upregulation and downregulation of several genes in the vicinity of its binding sites (Pauli et al, 2010). How cohesin and changes to its expression levels result in distinct transcriptional outcomes at individual gene loci and in different cell types is incompletely understood (Schaaf et al, 2009).In zebrafish, cohesin has been shown to positively regulate the Runx transcription factors, which determine cell fate during early embryonic development. Downregulation of the Scc1 or Smc3 cohesin subunits leads to aberrant expression of Runx proteins in a dose-dependent manner, despite cell division being able to proceed (Horsfield et al, 2007).…”