![]() EHMT1 is the primary enzyme for dimethylation of histone H3 at Lys9 residues (H3K9me2) and is generally associated with transcriptional gene silencing. Consistent with an epigenetic origin of KS, a broader Kleefstra syndrome phenotypic spectrum (KSS) is also associated with other chromatin modifiers, including ML元 (KMT2C). This region contains at least five genes, including ZMYND19, ARRDC1, C9ORF37, EHMT1, and CACNA1B, however, the core clinical phenotypes are driven by haploinsufficiency of EHMT1. To address this question, we have investigated the mechanism by which reduced EHMT1 activity leads to an altered neurodevelopmental programme in both isogenic cell models of Kleefstra syndrome and patient-derived iPSC.Ĭanonical Kleefstra syndrome (KS) arises from a sub-telomeric microdeletion at 9q34, resulting in a heterozygous deletion of approximately ∼700-kb. Although the genetic case for epigenetic regulation is well established, there is little knowledge of the downstream molecular mechanisms that link their actions to the underlying pathophysiology of the NDD. A recent study indicates an association of de novo postzygotic EHMT1 mutation and an ASD and neurocognitive dysfunctions in adults. KS is associated with autistic features, psychosis, and schizophrenia. The latter is subject of this study and here referred by its common name, Euchromatic Histone-Lysine N-Methyltransferase 1 or EHMT1. Other KMT are linked to severe neurodevelopmental disruption and ID associated genetic syndromes KMT2A with Wiedemann-Steiner Syndrome, KMT2D with Kabuki Syndrome and KMT1D with Kleefstra syndrome (KS). LOF variants of the H3K4 methyltransferase SETD1A are associated with schizophrenia, developmental delay (DD) and ID. LOF mutations of ML元 (KMT2C), MLL5 (KMT2E), ASH1L (KMT2H), SUV420H1 (KMT5B) and histone lysine demethylases (KDM), KDM5B and KDM6B are all associated with ASD. Histone lysine methyltransferases (KMT) are key epigenetic regulators, and many are associated with NDD and psychiatric disorders. Disruption of the SNF-2 family chromatin re-modellers CHD7 and CHD8 are strongly associated with ID and along with CHD2 confer risk for ASD. ![]() Studies on high risk, loss of function (LOF) gene variants associated with NDD reinforce this view. Epigenetic-related risk alleles are linked with biological pathways that converge on chromatin regulation via control of nucleosome positioning and histone methylation, leading to altered gene transcription. Accordingly, alleles affecting epigenetic regulatory mechanisms are associated with a range of psychiatric symptoms, including cognitive deficits, autistic traits, and psychosis. These often encompass more than one condition, including Intellectual Disability (ID), autism spectrum disorders (ASD) and schizophrenia. Genome-wide association studies (GWAS) have revealed multiple risk loci for neurodevelopmental disorders (NDD) that are associated with genes encoding epigenetic regulators. Genetic evidence points to an association of chromatin remodellers, mediators of epigenetic regulation, as a substantial risk factor for many common psychiatric disorders. This reveals a broad molecular interaction between H3K9 demethylation, NSRF/REST regulation and risk for ID and Schizophrenia. Significantly, the EHMT1-regulated miRNA gene set not only controls NRSF/REST but is enriched for association for Intellectual Disability (ID) and schizophrenia. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA and leads to aberrant neuronal gene regulation and neurodevelopment timing. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a genetic disorder linked with neurodevelopmental disorders and associated with schizophrenia. 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.
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