The HUSH complex controls brain architecture and protocadherin fidelity.
Astrid HagelkruysMarion HorrerJasmin Taubenschmid-StowersAnoop M KavirayaniMaria NovatchkovaMichael OrthoferTsung-Pin PaiDomagoj CikesSergei ZhukMeritxell BalmañaChristopher EskRubina KoglgruberPaul MoesenederJelena LazovicLydia M ZopfShane J F CroninUlrich EllingJürgen Arthur KnoblichJosef M PenningerPublished in: Science advances (2022)
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 Mphosph8 or Morc2a 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.
Keyphrases
- resting state
- white matter
- cerebral ischemia
- binding protein
- endothelial cells
- functional connectivity
- induced pluripotent stem cells
- high frequency
- subarachnoid hemorrhage
- genome wide
- high fat diet induced
- copy number
- multiple sclerosis
- big data
- insulin resistance
- pluripotent stem cells
- machine learning
- deep learning
- metabolic syndrome
- data analysis
- wild type
- genome wide analysis