Autism spectrum disorders (ASD) are associated with defects in neuronal connectivity and are highly heritable. Genetic findings suggest that there is an overrepresentation of chromatin regulatory genes among the genes associated with ASD. ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for ASD. ASH1L methylates Histone H3 on Lysine 36, which is proposed to result primarily in transcriptional activation. However, how mutations in ASH1L lead to deficits in neuronal connectivity associated with ASD pathogenesis is not known. We report that ASH1L regulates neuronal morphogenesis by counteracting the catalytic activity of Polycomb Repressive complex 2 group (PRC2) in stem cell-derived human neurons. Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis. The neuronal morphogenesis defect is overcome by inhibition of PRC2 activity, indicating that a balance between the Trithorax group protein ASH1L and PRC2 activity determines neuronal morphology. Thus, our work suggests that ASH1L may epigenetically regulate neuronal morphogenesis by modulating pathways like the BDNF-TrkB signaling pathway. Defects in neuronal morphogenesis could potentially impair the establishment of neuronal connections which could contribute to the neurodevelopmental pathogenesis associated with ASD in patients with ASH1L mutations.
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We thank Jeff Twiss for critically reading the manuscript, Amar Kar for insightful discussions on this work, and members of the Twiss laboratory for advice and training on ddPCR. iPSC line 20b was a kind gift of Dr. Kevin Eggan (Harvard Medical School). SBL was supported in part by the Center of Biomedical Excellence Dietary Supplements and Inflammation-NIGMS P20GM103641, SC INBRE NIGMS P20GM103499, and the SC EPSCoR/IDeA Program under award number 18-SR04. The views, perspective, and content do not necessarily represent the official views of the SC EPSCoR/IDeA Program. JSL is supported by 1R01NS104428-01A1. Diagram illustrations were made using BioRender.com
The authors declare no competing interests.
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Cheon, S., Culver, A.M., Bagnell, A.M. et al. Counteracting epigenetic mechanisms regulate the structural development of neuronal circuitry in human neurons. Mol Psychiatry 27, 2291–2303 (2022). https://doi.org/10.1038/s41380-022-01474-1