Chromosome Instability and Dynamics Lab. The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Cancer Genomics and Biocomputing of Complex Diseases Lab. The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Sci Rep. 2019 Jun 20;9(1):8929. doi: 10.1038/s41598-019-45263-3.
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.
Chd1 是一种染色质重塑因子，参与核小体定位和转录。CHD1 的缺失是前列腺癌的一个常见事件。结构维持染色体 (SMC) 复合物黏合蛋白介导长距离染色质相互作用，并参与维持基因组稳定性。我们提供了新的证据表明 Chd1 是黏合蛋白的调节剂。在酵母 S. cerevisiae 中，Chd1 不是生存所必需的。我们表明，该基因的缺失会导致姐妹染色单体黏合和染色体形态缺陷。Chl1 是一种非必需的 DNA 解旋酶，已被证明可以调节黏合蛋白的加载。令人惊讶的是，Chd1 和 Chl1 的共同缺失导致黏合缺陷的累加，但对染色体结构表型的部分抑制。我们发现，当 Chd1 和 Chl1 缺失时，黏合蛋白调节因子 Pds5 过表达。然而，当这两个基因都缺失时，Pds5 的表达降低到野生型水平。最后，我们在前列腺癌患者中观察到 CHD1 和黏合蛋白基因表达之间的相关性。此外，我们表明黏合蛋白亚基的过表达与肿瘤的侵袭性相关。讨论了 Chd1、Chl1 和 SMCs 之间相互作用的生物学作用。
