Dysregulation of NRSF/REST via EHMT1 is association with psychiatric disorders

Alsaqati, M.; Davis, B. A.; Wood, J.; Jones, M.; Jones, L.; Petter, O.; Isles, A. R.; Linden, D.; van den Bree, M. B.; Owen, M.; Hall, J.; Harwood, A. J.

doi:10.1101/2021.04.26.441439

bioRxiv · 10.1101/2021.04.26.441439

Dysregulation of NRSF/REST via EHMT1 is association with psychiatric disorders

Alsaqati, M.·Davis, B. A.·Wood, J.·Jones, M.·Jones, L.·Petter, O.·Isles, A. R.·Linden, D.·van den Bree, M. B.·Owen, M.·Hall, J.·Harwood, A. J.

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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 are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is 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 leading 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. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

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Alsaqati, M., Davis, B. A., Wood, J., Jones, M., Jones, L., Petter, O., Isles, A. R., Linden, D., van den Bree, M. B., Owen, M., Hall, J., Harwood, A. J.. 2021-04-26. Dysregulation of NRSF/REST via EHMT1 is association with psychiatric disorders. https://doi.org/10.1101/2021.04.26.441439

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