Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A, and RAD21, cohesin in somatic cells contains one of two orthologous STAG subunits, STAG1 or STAG2. How these variable subunits affect the function of the cohesin complex is still unclear. STAG1- and STAG2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of STAG1 and STAG2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either STAG1 or STAG2. Following rapid depletion of either subunit, we perform high-resolution Hi-C, gene expression, and sequential ChIP studies to show that STAG1 and STAG2 do not co-occupy individual binding sites and have distinct ways by which they affect looping and gene expression. These findings are further supported by single-molecule localizations via direct stochastic optical reconstruction microscopy (dSTORM) super-resolution imaging. Since somatic and congenital mutations of the STAG subunits are associated with cancer (STAG2) and intellectual disability syndromes with congenital abnormalities (STAG1 and STAG2), we verified STAG1-/STAG2-dependencies using human neural stem cells, hence highlighting their importance in particular disease contexts.

中文翻译：

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黏着蛋白STAG亚基在染色质环化和转录控制中的冗余和特定作用。

粘着蛋白是一种环状的多蛋白复合物，在分化和发育过程中对于3D基因组的组织和转录调控至关重要。它还赋予姐妹染色单体内聚力，并促进DNA损伤修复。除了其核心亚基SMC3，SMC1A和RAD21，体细胞中的粘附素还包含两个直系同源STAG亚基之一，即STAG1或STAG2。这些可变亚基如何影响粘着蛋白复合物的功能仍不清楚。最初提出STAG1-和STAG2-cohesin分别组织端粒和着丝粒的内聚力。在这里，我们发现使用带有生长素诱导型degron（AID）标签融合到STAG1或STAG2的HCT116细胞，STAG1和STAG2在基因调控和染色质环化中的冗余和特定作用。快速耗尽任何一个亚基后，我们将执行高分辨率的Hi-C，基因表达和顺序ChIP研究表明STAG1和STAG2不会共同占据单个结合位点，并且具有影响环和基因表达的独特方式。通过直接随机光学重建显微镜（dSTORM）超分辨率成像的单分子定位进一步支持了这些发现。由于STAG亚基的体细胞和先天性突变与癌症（STAG2）和具有先天性异常的智力障碍综合症（STAG1和STAG2）相关，我们使用人类神经干细胞验证了STAG1- / STAG2依赖性，因此强调了它们在特定疾病中的重要性上下文。通过直接随机光学重建显微镜（dSTORM）超分辨率成像的单分子定位进一步支持了这些发现。由于STAG亚基的体细胞和先天性突变与癌症（STAG2）和具有先天性异常的智力障碍综合症（STAG1和STAG2）相关，我们使用人类神经干细胞验证了STAG1- / STAG2依赖性，因此强调了它们在特定疾病中的重要性上下文。通过直接随机光学重建显微镜（dSTORM）超分辨率成像的单分子定位进一步支持了这些发现。由于STAG亚基的体细胞和先天性突变与癌症（STAG2）和具有先天性异常的智力障碍综合症（STAG1和STAG2）相关，我们使用人类神经干细胞验证了STAG1- / STAG2依赖性，因此强调了它们在特定疾病中的重要性上下文。