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

Autor: Mouhamed Alsaqati, Brittany A. Davis, Jamie Wood, Megan M. Jones, Lora Jones, Aishah Westwood, Olena Petter, Anthony R. Isles, David Linden, Marianne Van den Bree, Michael Owen, Jeremy Hall, Adrian J. Harwood
Přispěvatelé: RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Translational Psychiatry, 12(1):438. Nature Publishing Group
ISSN: 2158-3188
DOI: 10.1038/s41398-022-02199-z
Popis: 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.
Databáze: OpenAIRE
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