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NRSF/REST lies at the intersection between epigenetic regulation, miRNA-mediated gene control and neurodevelopmental pathways associated with Intellectual disability (ID) and Schizophrenia

Lookup NU author(s): Dr Mouhamed AlsaqatiORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022, The Author(s).Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association remain to be determined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a genetic disorder linked with neurodevelopmental disorders and associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA and leads to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Significantly, the EHMT1-regulated miRNA gene set not only controls NRSF/REST but is enriched for association for Intellectual Disability (ID) and schizophrenia. This reveals a broad molecular interaction between H3K9 demethylation, NSRF/REST regulation and risk for ID and Schizophrenia.

Publication metadata

Author(s): Alsaqati M, Davis BA, Wood J, Jones MM, Jones L, Westwood A, Petter O, Isles AR, Linden D, Van den Bree M, Owen M, Hall J, Harwood AJ

Publication type: Article

Publication status: Published

Journal: Translational Psychiatry

Year: 2022

Volume: 12

Issue: 1

Print publication date: 01/12/2022

Online publication date: 10/10/2022

Acceptance date: 21/09/2022

Date deposited: 25/10/2022

ISSN (electronic): 2158-3188

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41398-022-02199-z

DOI: 10.1038/s41398-022-02199-z

PubMed id: 36216811

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