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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Article number438
Number of pages10
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 10 Oct 2022


  • Epigenesis, Genetic
  • Humans
  • Intellectual Disability/genetics
  • MicroRNAs/genetics
  • RNA, Messenger/genetics
  • Repressor Proteins/genetics
  • Schizophrenia/genetics

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