Epigenetic mechanisms of disrupted neurodevelopment in Menke-Hennekam syndrome

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Project Summary Heterozygous variants in EP300, a histone acetyltransferase, cause two rare multi-organ chromatinopathies: Menke-Hennekam syndromes type 2 (MKHK2; MIM618333, specifically mutations in exon 30-31) and Rubinstein-Taybi type 2 (RSTS2; MIM613684). Interestingly, based on “inverse” patient craniofacial characteristics with RSTS and the alignment of MKHK2 facial features with another disorder with duplicated regions of CREBBP (EP300's paralog), authors have proposed mutations causing MKHK and RSTS have potentially different functions (i.e., gain [GOF] versus loss [LOF], respectively).1,2 In addition, individuals with MKHK2 have overlapping manifestations with disorders with malformations in cortical development (MCD), such as microencephaly, seizures, intellectual disability, repetitive behaviors, and increased rates of co-diagnoses with autism spectrum disorder, demonstrating a potential role in cortical neuron function.3 While the specialized exon 30-31 missense mutations found in MKHK2 have yet to be modeled, RSTS2 LOF models have yielded phenotypic changes of shorter branches and hypo-excitability. However, the RSTS2 LOF bulk neuronal bioinformatical analyses contained contaminating cell types with differential regional specificity, therefore, EP300 specific gene network/pathways are uninterpretable. Together this demonstrates a critical need to understand EP300's role in maturation and function of cortical excitatory neurons before treatment of MKHK2 neurological issues can be tackled. We hypothesize that MKHK2 EP300 mutation causes accelerated maturation rate, decreased dendrite formation, and altered neuronal function. This proposal is a collaboration between Drs. Potter and Barski who specialize in epigenomics and Dr. Tchieu, a developmental biologist who developed methods for human induced pluripotent stem cell (hPSC) differentiation into nervous system cell types. In this study, we will use this approach to differentiate MKHK2 mutated EP300 and corresponding isogenic control hPSCs into radial glia-like neural stem cells and PFC excitatory neurons in order to: (1) identify MKHK2-related defects in neuronal maturation and signaling and (2) to identify epigenetic and gene expression changes driving them. This pilot project will provide a solid foundation for the study of the mechanism(s) behind neurocortical developmental defects in MKHK2 and allow identification of molecular targets for potential therapies for MKHK2 seizures and other related MCD-like symptoms. Further, we can apply knowledge and technical expertise gained from this project to other epigenetic proteins to further expand our knowledge of epigenetic regulation during corticogenesis, specifically neuronal maturation and signaling allowing for a broader impact on the treatment of MCD, neurodegenerative, neurodevelopment, and neuroinflammatory disorders.