Laboratory of Epigenetics and Chromatin Dynamics, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC B11, Lund University, Lund, Sweden.
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC A11, Lund University, Lund, Sweden.
Nat Commun. 2024 Aug 30;15(1):7534. doi: 10.1038/s41467-024-50765-4.
The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. How HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains largely unknown. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding, and simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.
人类沉默枢纽 (HUSH) 复合物与 LINE-1 反转录转座子 (L1s) 和其他基因组重复序列的转录本结合，招募 MORC2 和其他效应因子重塑染色质。HUSH 和 MORC2 如何与 DNA 甲基化（重复转录的主要表观遗传调节剂）协同作用，在很大程度上仍不清楚。在这里，我们在人神经祖细胞 (hNPCs) 中研究了这种关系，hNPCs 是大脑发育的体细胞模型，可耐受 DNA 甲基转移酶 DNMT1 的缺失。在 hNPCs 中失去 MORC2 或 HUSH 亚基 TASOR 后，L1 仍通过强大的启动子甲基化沉默。然而，基因组去甲基化和进化年轻的 L1 的激活吸引了 MORC2 结合，同时耗尽 DNMT1 和 MORC2 会导致大量 L1 转录本的积累。我们在着丝粒周围的 α-卫星和聚集的原钙粘蛋白基因中发现了相同的机制层次结构，这些重复元件分别对染色体结构和神经发育很重要。我们的数据描绘了体细胞中重复序列的表观遗传控制，这对于理解 HUSH-MORC2 在人类发育过程中整个低甲基化环境中的重要功能具有重要意义。
