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The HUSH complex controls brain architecture and protocadherin fidelity
Astrid Hagelkruys1, Marion Horrer1, Jasmin Taubenschmid-Stowers1
1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
Science Advances
|November 4, 2022
Summary
The HUSH complex proteins MPP8 and MORC2 regulate brain development by suppressing protocadherin genes. Their inactivation in mice caused larger brains and altered architecture, revealing their crucial in vivo roles.
Area of Science:
- Epigenetics and Gene Regulation
- Neuroscience and Developmental Biology
Background:
- The HUSH (human silencing hub) complex is involved in gene silencing.
- Previous research focused on SETDB1 within the HUSH complex, leaving the in vivo functions of MPP8 and MORC2 largely unknown.
Purpose of the Study:
- To investigate the in vivo functions of MPP8 and MORC2 in the nervous system.
- To elucidate the mechanistic role of MPP8 and MORC2 in brain development and gene expression.
Main Methods:
- Genetic inactivation of Mphosph8 and Morc2a in mouse nervous systems.
- Analysis of brain size, architecture, and behavior in knockout mice.
- Investigation in human cerebral organoids to confirm findings.
Main Results:
- Genetic inactivation of MPP8 or MORC2 led to increased brain size, altered brain architecture, and behavioral changes in mice.
- MPP8 and MORC2 were found to suppress the protocadherin gene cluster in an H3K9me3-dependent manner in both mouse brains and human cerebral organoids.
Conclusions:
- MPP8 and MORC2 are key epigenetic regulators of protocadherin expression in the nervous system.
- These proteins play critical roles in brain development and establishing neuronal individuality.
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