Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, NC, USA.
Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, USA.
BMC Genomics. 2022 Apr 30;23(1):337. doi: 10.1186/s12864-022-08574-w.
The cohesin complex is essential for proper chromosome structure and gene expression. Defects in cohesin subunits and regulators cause changes in cohesin complex dynamics and thereby alter three-dimensional genome organization. However, the molecular mechanisms that drive cohesin localization and function remain poorly understood.
In this study, we observe that loss of WIZ causes changes to cohesin localization that are distinct from loss of the known WIZ binding partner G9a. Whereas loss of WIZ uniformly increases cohesin levels on chromatin at known binding sites and leads to new, ectopic cohesin binding sites, loss of G9a does not. Ectopic cohesin binding on chromatin after the loss of WIZ occurs at regions that are enriched for activating histone modifications and transcription factors motifs. Furthermore, loss of WIZ causes changes in cohesin localization that are distinct from those observed by loss of WAPL, the canonical cohesin unloading factor.
The evidence presented here suggests that WIZ can function independently from its previously identified role with G9a and GLP in heterochromatin formation. Furthermore, while WIZ limits the levels and localization pattern of cohesin across the genome, it appears to function independently of WAPL-mediated cohesin unloading.
黏合蛋白复合物对于染色体结构和基因表达的正常运作至关重要。黏合蛋白亚基和调节因子的缺陷会导致黏合蛋白复合物的动力学发生变化，从而改变三维基因组的组织。然而，驱动黏合蛋白定位和功能的分子机制仍知之甚少。
在这项研究中，我们观察到 WIZ 的缺失会导致黏合蛋白定位的改变，这与已知的 WIZ 结合伴侣 G9a 的缺失不同。WIZ 的缺失会均匀地增加染色质上已知结合位点的黏合蛋白水平，并导致新的、异位的黏合蛋白结合位点，而 G9a 的缺失则不会。WIZ 缺失后，在富含激活组蛋白修饰和转录因子基序的区域发生染色质上的异位黏合蛋白结合。此外，WIZ 的缺失会导致黏合蛋白定位的改变，这与 WAPL（典型的黏合蛋白卸载因子）缺失所观察到的改变不同。
这里提出的证据表明，WIZ 可以独立于其先前与 G9a 和 GLP 共同在异染色质形成中的作用发挥功能。此外，虽然 WIZ 限制了基因组中黏合蛋白的水平和定位模式，但它似乎独立于 WAPL 介导的黏合蛋白卸载功能。
