Hagelkruys Astrid, Horrer Marion, Taubenschmid-Stowers Jasmin, Kavirayani Anoop, Novatchkova Maria, Orthofer Michael, Pai Tsung-Pin, Cikes Domagoj, Zhuk Sergei, Balmaña Meritxell, Esk Christopher, Koglgruber Rubina, Moeseneder Paul, Lazovic Jelena, Zopf Lydia M, Cronin Shane J F, Elling Ulrich, Knoblich Jürgen A, Penninger Josef M
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
Vienna Biocenter Core Facilities (VBCF), Vienna, Austria.
Sci Adv. 2022 Nov 4;8(44):eabo7247. doi: 10.1126/sciadv.abo7247.
The HUSH (human silencing hub) complex contains the H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and recruits the histone methyltransferase SETDB1 as well as Microrchidia CW-type zinc finger protein 2 (MORC2). Functional and mechanistic studies of the HUSH complex have hitherto been centered around SETDB1 while the in vivo functions of MPP8 and MORC2 remain elusive. Here, we show that genetic inactivation of or in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, in both mouse brains and human cerebral organoids, MPP8 and MORC2 suppress the repetitive-like protocadherin gene cluster in an H3K9me3-dependent manner. Our data identify MPP8 and MORC2, previously linked to silencing of repetitive elements via the HUSH complex, as key epigenetic regulators of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.
HUSH（人类沉默枢纽）复合物包含H3K9me3结合蛋白M期磷酸化蛋白8（MPP8），并招募组蛋白甲基转移酶SETDB1以及微精蛋白CW型锌指蛋白2（MORC2）。迄今为止，对HUSH复合物的功能和机制研究主要集中在SETDB1上，而MPP8和MORC2在体内的功能仍不清楚。在这里，我们表明，小鼠神经系统中MPP8或MORC2的基因失活会导致脑容量增加、脑结构改变和行为变化。从机制上讲，在小鼠大脑和人类大脑类器官中，MPP8和MORC2均以H3K9me3依赖的方式抑制类重复原钙黏蛋白基因簇。我们的数据确定了先前通过HUSH复合物与重复元件沉默相关的MPP8和MORC2，它们是神经系统中原钙黏蛋白表达的关键表观遗传调节因子，从而也是小鼠和人类大脑发育和神经元个体性的关键表观遗传调节因子。
