Abstract
Chd1 is a chromatin remodeler that is involved in nucleosome positioning and transcription. Deletion of CHD1 is a frequent event in prostate cancer. The Structural Maintenance of Chromosome (SMC) complex cohesin mediates long-range chromatin interactions and is involved in maintaining genome stability. We provide new evidence that Chd1 is a regulator of cohesin. In the yeast S. cerevisiae, Chd1 is not essential for viability. We show that deletion of the gene leads to a defect in sister chromatid cohesion and in chromosome morphology. Chl1 is a non-essential DNA helicase that has been shown to regulate cohesin loading. Surprisingly, co-deletion of CHD1 and CHL1 results in an additive cohesion defect but partial suppression of the chromosome structure phenotype. We found that the cohesin regulator Pds5 is overexpressed when Chd1 and Chl1 are deleted. However, Pds5 expression is reduced to wild type levels when both genes are deleted. Finally, we show a correlation in the expression of CHD1 and cohesin genes in prostate cancer patients. Furthermore, we show that overexpression of cohesin subunits is correlated with the aggressiveness of the tumor. The biological roles of the interplay between Chd1, Chl1 and SMCs are discussed.
Highlights
The evolutionary conserved Chd[1] gene encodes for an ATP-dependent chromatin-remodeling factor, which contains a chromodomain, a DNA binding domain and a DEAH helicase domain (Fig. 1)[1,2,3]
Was observed in 24% of the nuclei, and the percentage of normal loop morphology was ~60% (Fig. 3B). These results suggest that Chd[1] and Chl[1] regulate the size of the rDNA loop and have opposing effects on its morphology
Pds[5] levels were reduced back to the wild type level when both CHD1 and CHL1 were deleted (Fig. 5). These results suggest that Chd[1] and Chl[1] affect cohesin indirectly by altering the complex stoichiometry
Summary
The evolutionary conserved Chd[1] gene encodes for an ATP-dependent chromatin-remodeling factor, which contains a chromodomain, a DNA binding domain and a DEAH helicase domain (Fig. 1)[1,2,3]. The Chl[1] helicase has been shown to regulate cohesin, and deletion of this gene results in a similar mild cohesion loss[25,26,27,28,29]. We sought to compare the cohesion loss in chd1Δ cells to the effect of CHL1 deletion. Cohesin levels on the chromatin are reduced in CHD1 and CHL1 deleted cells.
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