Cargando…
The HUSH complex controls brain architecture and protocadherin fidelity
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 cente...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635835/ https://www.ncbi.nlm.nih.gov/pubmed/36332029 http://dx.doi.org/10.1126/sciadv.abo7247 |
_version_ | 1784824799543951360 |
---|---|
author | 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. |
author_facet | 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. |
author_sort | Hagelkruys, Astrid |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9635835 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-96358352022-11-18 The HUSH complex controls brain architecture and protocadherin fidelity 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. Sci Adv Neuroscience 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. American Association for the Advancement of Science 2022-11-04 /pmc/articles/PMC9635835/ /pubmed/36332029 http://dx.doi.org/10.1126/sciadv.abo7247 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Neuroscience 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. The HUSH complex controls brain architecture and protocadherin fidelity |
title | The HUSH complex controls brain architecture and protocadherin fidelity |
title_full | The HUSH complex controls brain architecture and protocadherin fidelity |
title_fullStr | The HUSH complex controls brain architecture and protocadherin fidelity |
title_full_unstemmed | The HUSH complex controls brain architecture and protocadherin fidelity |
title_short | The HUSH complex controls brain architecture and protocadherin fidelity |
title_sort | hush complex controls brain architecture and protocadherin fidelity |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635835/ https://www.ncbi.nlm.nih.gov/pubmed/36332029 http://dx.doi.org/10.1126/sciadv.abo7247 |
work_keys_str_mv | AT hagelkruysastrid thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT horrermarion thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT taubenschmidstowersjasmin thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT kavirayanianoop thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT novatchkovamaria thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT orthofermichael thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT paitsungpin thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT cikesdomagoj thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT zhuksergei thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT balmanameritxell thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT eskchristopher thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT koglgruberrubina thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT moesenederpaul thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT lazovicjelena thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT zopflydiam thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT croninshanejf thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT ellingulrich thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT knoblichjurgena thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT penningerjosefm thehushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT hagelkruysastrid hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT horrermarion hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT taubenschmidstowersjasmin hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT kavirayanianoop hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT novatchkovamaria hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT orthofermichael hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT paitsungpin hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT cikesdomagoj hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT zhuksergei hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT balmanameritxell hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT eskchristopher hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT koglgruberrubina hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT moesenederpaul hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT lazovicjelena hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT zopflydiam hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT croninshanejf hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT ellingulrich hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT knoblichjurgena hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity AT penningerjosefm hushcomplexcontrolsbrainarchitectureandprotocadherinfidelity |