An Hongjoo, Fan Chuandong, Kim Dongkyeong, Bui Huy, Park Yungki
Institute for Myelin and Glia Exploration, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America.
PLoS Genet. 2025 Jul 11;21(7):e1011778. doi: 10.1371/journal.pgen.1011778. eCollection 2025 Jul.
Oligodendrocytes (OLs) assemble myelin sheaths around axons in central nervous system (CNS). Myelin is essential for the saltatory conduction of action potentials and also performs other critical functions for the operation of the CNS. Sox10 (SRY-box containing gene 10) is a high-mobility group transcription factor that orchestrates the development of OLs. Despite its key role in OL biology, there is scant information on how the expression of Sox10 is regulated in OL lineage cells. Especially, OL enhancers that control its transcription remain elusive. We have recently developed an innovative method that rationally links OL enhancers to target genes. This study applied the new method to Sox10, uncovering two OL enhancers for it (termed Sox10-E1 and Sox10-E2). Epigenome editing analysis revealed that Sox10-E1 and Sox10-E2 regulate Sox10 expression non-redundantly. Luciferase assay and human and mouse brain multi-omics data show that, during the differentiation of OL precursor cells (OPCs) into OLs, the enhancer activity of Sox10-E1 does not change while that of Sox10-E2 decreases significantly. Chromatin interaction data indicate that the two Sox10 enhancers lie close to the border of the Sox10 topologically associating domain (TAD). Consistently, Pick1, a gene that is near the Sox10 TAD border, is also under the transcriptional control of Sox10-E1 and Sox10-E2. Hence, genomic deletions involving Sox10-E1 and Sox10-E2 would perturb not only SOX10, but also PICK1 and other genes, and may cause a pathology that is more complex than that of conventional Waardenburg-Shah syndrome that results from SOX10 coding mutations.
少突胶质细胞（OLs）在中枢神经系统（CNS）中围绕轴突组装髓鞘。髓鞘对于动作电位的跳跃式传导至关重要，并且对CNS的运作还执行其他关键功能。Sox10（含SRY盒基因10）是一种高迁移率族转录因子，它协调OLs的发育。尽管其在OL生物学中起关键作用，但关于Sox10在OL谱系细胞中的表达如何被调控的信息却很少。特别是，控制其转录的OL增强子仍然难以捉摸。我们最近开发了一种创新方法，该方法合理地将OL增强子与靶基因联系起来。本研究将这种新方法应用于Sox10，发现了两个针对它的OL增强子（称为Sox10-E1和Sox10-E2）。表观基因组编辑分析表明，Sox10-E1和Sox10-E2非冗余地调节Sox10表达。荧光素酶测定以及人和小鼠脑多组学数据表明，在OL前体细胞（OPCs）分化为OLs的过程中，Sox10-E1的增强子活性不变，而Sox10-E２的增强子活性显著降低。染色质相互作用数据表明，这两个Sox10增强子位于Sox10拓扑相关结构域（TAD）的边界附近。一致的是，位于Sox10 TAD边界附近的基因Pick1也受Sox10-E1和Sox10-E2的转录调控。因此，涉及Sox10-E1和Sox10-E2的基因组缺失不仅会扰乱SOX10，还会扰乱PICK1和其他基因，并可能导致比由SOX10编码突变引起的传统瓦登伯革-沙阿综合征更复杂的病理情况。
