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

Alsaqati, Mouhamed, Davis, Brittany A., Wood, Jamie, Jones, Megan M., Jones, Lora, Westwood, Aishah, Petter, Olena, Isles, Anthony R. ORCID: https://orcid.org/0000-0002-7587-5712, Linden, David ORCID: https://orcid.org/0000-0002-5638-9292, Van den Bree, Marianne ORCID: https://orcid.org/0000-0002-4426-3254, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009 and Harwood, Adrian J. ORCID: https://orcid.org/0000-0003-3124-5169 2022. NRSF/REST lies at the intersection between epigenetic regulation, miRNA-mediated gene control and neurodevelopmental pathways associated with Intellectual disability (ID) and Schizophrenia. Translational Psychiatry 12 , 438. 10.1038/s41398-022-02199-z

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Springer Nature [academic journals on nature.com]
Funders:	Wellcome Trust
Date of First Compliant Deposit:	12 October 2022
Date of Acceptance:	21 September 2022
Last Modified:	27 Feb 2024 12:29
URI:	https://orca.cardiff.ac.uk/id/eprint/153344

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