The HUSH complex controls brain architecture and protocadherin fidelity

Abstract

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.

Distinct epigenetic modulation of differentially expressed genes in the adult mouse brain following prenatal exposure to low-dose bisphenol A

“…Consistent results were revealed (Fig. S5 H) when we performed additional ChromHMM analysis using different sets of published ChIP-seq (ENCODE Project Consortium 2012 ; Hagelkruys et al 2022 ; Mo et al 2015 ) and ATAC-seq data (Stroud et al 2020 ).…”

CDCA7-associated global aberrant DNA hypomethylation translates to localized, tissue-specific transcriptional responses

“…Likely, the activity of Pcdh gene cluster members needs to be tightly controlled by several layers of epigenetic regulation to achieve cell type–specific stochastic expression. Consistent with this hypothesis are previous studies by others and us, which identified the cPcdh genes as targets of the de novo DNA methyltransferase DNMT3B ( 35 ), the human silencing hub (HUSH) complex ( 41 , 42 ) and the cohesion/CTCF complex member widely interspaced ZF motifs (WIZ) ( 68 , 69 ) via in vivo genetic approaches. Furthermore, CTCF is critical for cPcdh regulation by mediating promoter-enhancer interactions ( 43 , 70 ).…”

“…At the molecular level, both H3K9me3 ( 41 , 42 ) and DNA methylation pathways ( 35 , 43 ) have been implicated in the regulation of Pcdha expression and stochastic isoform choice. Using Sanger bisulfite sequencing, we found reduced Pcdha promoter DNA methylation levels in Cdca7 G305V mutant cerebrum at all variable isoforms tested (Fig.…”

Destabilization of microrchidia family CW‐type zinc finger 2 via the cyclin‐dependent kinase 1‐chaperone‐mediated autophagy pathway promotes mitotic arrest and enhances cancer cellular sensitivity to microtubule‐targeting agents

“…Microrchidia family CW‐type zinc finger 2 (MORC2) is a newly identified chromatin‐remodelling enzyme and has fundamental functions in gene transcription and DNA damage repair. As a component of the human silencing hub (HUSH) complex, MORC2 affects HUSH‐mediated epigenetic gene silencing 27–29 . In addition, recent work from our group demonstrated that MORC2 is involved in DNA damage response and contributes to the resistance of breast cancer cells to DNA‐damaging agents 30–34 .…”

“…As a component of the human silencing hub (HUSH) complex, MORC2 affects HUSH‐mediated epigenetic gene silencing. 27 , 28 , 29 In addition, recent work from our group demonstrated that MORC2 is involved in DNA damage response and contributes to the resistance of breast cancer cells to DNA‐damaging agents. 30 , 31 , 32 , 33 , 34 Notably, mutations in MORC2 have been linked to several human diseases, including Charcot‐Marie‐Tooth disease, 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 Cockayne syndrome, 43 neurodevelopmental disorder, 44 motor neuropathy 45 and triple‐negative breast cancer.…”