Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, State University of New York at Buffalo, Buffalo, NY 14203, United States.
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, United States.
Hum Mol Genet. 2023 Nov 17;32(23):3225-3236. doi: 10.1093/hmg/ddad141.
Oligodendrocytes (OLs) produce myelin sheaths around axons in the central nervous system (CNS). Myelin accelerates the propagation of action potentials along axons and supports the integrity of axons. Impaired myelination has been linked to neurological and neuropsychiatric disorders. As a major component of CNS myelin, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) plays an indispensable role in the axon-supportive function of myelin. Notably, this function requires a high-level expression of CNP in OLs, as evidenced by downregulated expression of CNP in mental disorders and animal models. Little is known about how CNP expression is regulated in OLs. Especially, OL enhancers that govern CNP remain elusive. We have recently developed a powerful method that links OL enhancers to target genes in a principled manner. Here, we applied it to Cnp, uncovering two OL enhancers for it (termed Cnp-E1 and Cnp-E2). Epigenome editing analysis revealed that Cnp-E1 and Cnp-E2 are dedicated to Cnp. ATAC-seq and ChIP-seq data show that Cnp-E1 and Cnp-E2 are conserved OL-specific enhancers. Single cell multi-omics data that jointly profile gene expression and chromatin accessibility suggest that Cnp-E2 plays an important role in Cnp expression in the early stage of OL differentiation while Cnp-E1 sustains it in mature OLs.
少突胶质细胞（OLs）在中枢神经系统（CNS）中轴突周围产生髓鞘。髓鞘加速动作电位沿轴突的传播，并支持轴突的完整性。髓鞘形成障碍与神经和神经精神疾病有关。作为 CNS 髓鞘的主要成分，2'，3'-环核苷酸 3'-磷酸二酯酶（CNP）在髓鞘的轴突支持功能中起着不可或缺的作用。值得注意的是，这种功能需要 OL 中 CNP 的高水平表达，这一点从精神障碍和动物模型中 CNP 的下调表达中可以得到证明。目前还不太清楚 OL 中 CNP 的表达是如何调节的。特别是，调控 CNP 的 OL 增强子仍然难以捉摸。我们最近开发了一种强大的方法，可以将 OL 增强子与目标基因以有原则的方式联系起来。在这里，我们将其应用于 Cnp，发现了两个 Cnp 的 OL 增强子（称为 Cnp-E1 和 Cnp-E2）。表观基因组编辑分析表明，Cnp-E1 和 Cnp-E2 是专门针对 Cnp 的。ATAC-seq 和 ChIP-seq 数据显示，Cnp-E1 和 Cnp-E2 是保守的 OL 特异性增强子。联合分析基因表达和染色质可及性的单细胞多组学数据表明，Cnp-E2 在 OL 分化的早期阶段对 Cnp 的表达起着重要作用，而 Cnp-E1 在成熟的 OL 中维持其表达。
