STAG2 promotes the myelination transcriptional program in oligodendrocytes [RNA-seq]

Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelinationrelated genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelinationpromoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription. The submission contains two RNA-Seq experiments from brain hemispheres or isolated primary oligodendrocytes of Stag2f/y and Stag2f/y; Cre mice: quadruplicates for brain hemispheres and duplicates for primary oligodendrocytes of each genotype黏连蛋白（Cohesin）通过DNA环挤出过程折叠染色体。黏连蛋白介导的染色体环可通过多种机制调控基因转录，其中包括塑造远距离增强子-启动子相互作用。黏连蛋白亚基及其调控因子的突变会引发一类被称为黏连蛋白病（cohesinopathy）的人类发育疾病。脊椎动物体内的黏连蛋白复合物由SMC1、SMC3、RAD21以及STAG1或STAG2构成。为探究黏连蛋白的生理功能，我们构建了神经系统中特异性敲除Stag2的条件性敲除（conditional knockout, cKO）小鼠模型。Stag2条件性敲除小鼠表现出生长迟缓、神经功能缺陷及过早死亡的表型，该表型的部分诱因是神经纤维髓鞘形成不足。Stag2条件性敲除的少突胶质细胞会出现成熟延迟以及髓鞘相关基因表达下调的现象。缺失Stag2会减少少突胶质细胞中下调基因的启动子锚定环数量。由此可见，STAG2-黏连蛋白可在促髓鞘形成基因处形成启动子锚定环，进而促进这些基因的转录。本研究证实髓鞘形成缺陷是黏连蛋白病的致病因素之一，并确立了少突胶质细胞作为研究黏连蛋白调控转录机制的合适细胞类型。本数据集包含两项RNA测序（RNA-Seq）实验，样本取自Stag2f/y与Stag2f/y; Cre小鼠的大脑半球或分离的原代少突胶质细胞：各基因型的大脑半球样本设置4个生物学重复，原代少突胶质细胞样本设置2个生物学重复。