The interplay between miRNAs and chromatin regulators underpins premature differentiation within neurodevelopmental disorders (NDDs)

Neurodevelopmental disorders (NDDs), such as Schizophrenia, Autism and Intellectual disability (ID) possess a wide range of neurological and physiological phenotypes, often showing significant overlap. Epigenetic regulators, including miRNAs and chromatin modifiers, have long been proposed as a possible cause of the broad range of symptoms associated with NDDs. However, the inherent complexity within miRNA regulatory networks has made it challenging to identify the key miRNAs and their mRNA targets and how they lead to the molecular deficits seen in NDDs. Here we investigate a regulatory pathway that connects the epigenetic repressor EHMT1 to the miRNA network to control REST/NRSF protein expression and show that it controls the timing of neurodevelopment. By use of a novel strategy utilising multi-miR sponges we identify key miRNAs that regulate REST/NRSF in human induced pluripotent stem cells (iPSC) and demonstrate that they control unidirectional developmental progression from the pluripotent stage into early neurodevelopment and then neuronal differentiation. These results demonstrate a highly regulated interaction between epigenetic regulators and miRNAs that is crucial to control the timing neurodevelopment and impacts on the origins of NDDs.