Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Glia. 2023 Jun;71(6):1466-1480. doi: 10.1002/glia.24351. Epub 2023 Feb 15.
Schwann cell programming during myelination involves transcriptional networks that activate gene expression but also repress genes that are active in neural crest/embryonic differentiation of Schwann cells. We previously found that a Schwann cell-specific deletion of the EED subunit of the Polycomb Repressive Complex (PRC2) led to inappropriate activation of many such genes. Moreover, some of these genes become re-activated in the pro-regenerative response of Schwann cells to nerve injury, and we found premature activation of the nerve injury program in a Schwann cell-specific knockout of Eed. Polycomb-associated histone modifications include H3K27 trimethylation formed by PRC2 and H2AK119 monoubiquitination (H2AK119ub1), deposited by Polycomb repressive complex 1 (PRC1). We recently found dynamic regulation of H2AK119ub1 in Schwann cell genes after injury. Therefore, we hypothesized that H2AK119 deubiquitination modulates the dynamic polycomb repression of genes involved in Schwann cell maturation. To determine the role of H2AK119 deubiquitination, we generated a Schwann cell-specific knockout of the H2AK119 deubiquitinase Bap1 (BRCA1-associated protein). We found that loss of Bap1 causes tomacula formation, decreased axon diameters and eventual loss of myelinated axons. The gene expression changes are accompanied by redistribution of H2AK119ub1 and H3K27me3 modifications to extragenic sites throughout the genome. BAP1 interacts with OGT in the PR-DUB complex, and our data suggest that the PR-DUB complex plays a multifunctional role in repression of the injury program. Overall, our results indicate Bap1 is required to restrict the spread of polycomb-associated histone modifications in Schwann cells and to promote myelin homeostasis in peripheral nerve.
许旺细胞在髓鞘形成过程中的编程涉及转录网络，这些网络既能激活基因表达，也能抑制许旺细胞神经嵴/胚胎分化过程中活跃的基因。我们之前发现，多梳抑制复合物（PRC2）的 EED 亚基在许旺细胞中特异性缺失会导致许多此类基因的异常激活。此外，这些基因中的一些在许旺细胞对神经损伤的促再生反应中重新激活，我们发现 Eed 敲除的许旺细胞中神经损伤程序的过早激活。多梳相关的组蛋白修饰包括 PRC2 形成的 H3K27 三甲基化和 Polycomb 抑制复合物 1（PRC1）沉积的 H2AK119 单泛素化（H2AK119ub1）。我们最近发现，损伤后许旺细胞基因中 H2AK119ub1 的动态调节。因此，我们假设 H2AK119 去泛素化调节参与许旺细胞成熟的基因的动态多梳抑制。为了确定 H2AK119 去泛素化的作用，我们生成了许旺细胞特异性敲除 H2AK119 去泛素酶 Bap1（BRCA1 相关蛋白）。我们发现 Bap1 的缺失会导致轴突直径减小和髓鞘轴突的丢失。基因表达的变化伴随着 H2AK119ub1 和 H3K27me3 修饰在外显子间位点的重新分布，遍及整个基因组。BAP1 在 PR-DUB 复合物中与 OGT 相互作用，我们的数据表明 PR-DUB 复合物在抑制损伤程序方面发挥着多功能作用。总的来说，我们的结果表明 Bap1 是限制多梳相关组蛋白修饰在许旺细胞中扩散并促进周围神经髓鞘内稳态所必需的。
