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.
Highlights
The cohesin protein complex holds sister chromatids together, ensuring their proper segregation upon cell division [1,2,3]
Cohesin and RNA polymerase II (PolII) binding overlap extensively genome-wide, while cohesin shows a negative correlation with the H3K27Me3 mark made by the PRC2 Polycomb group (PcG) silencing complex [15]
While comparing the cohesin and H3K27Me3 patterns, we noted eight unusual regions of extensive overlap ranging in length from 4.8 to 80.9 kb in the genome of BG3 cells derived from central nervous system, and only two such regions in Sg4 cells of embryonic origin (Table S1)
Summary
The cohesin protein complex holds sister chromatids together, ensuring their proper segregation upon cell division [1,2,3]. Cohesin binds chromosomes throughout interphase, and several findings indicate that it regulates gene expression. The Drosophila Nipped-B protein that loads cohesin onto chromosomes facilitates activation of the cut and Ultrabithorax homeobox genes, and cohesin inhibits cut expression [6,7,8,9]. Drosophila cohesin facilitates expression of a steroid hormone receptor and axon pruning in non-dividing neurons [10,11], and the Rad cohesin subunit encoded by verthandi (vtd), was identified genetically by its opposing effect to Polycomb group (PcG) silencing of homeotic genes [12,13]. Rad facilitates expression of zebrafish Runx genes in a cell-type specific manner [14]
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