Histone H1 Variants Regulate Neurodevelopmental Transcriptional Programs in Autism and Schizophrenia with 16p11.2 CNV
Neurodevelopmental disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ), involve widespread transcriptional dysregulation. Copy number variations (CNVs) at 16p11.2 are among the strongest genetic risk factors for ASD and SCZ, yet the molecular mechanisms by which these CNV contribute to neurodevelopmental pathology remain unclear. Here, we identify significant genetic associations between ASD susceptibility and the HIST1 histone gene cluster through genome-wide analysis. Transcriptomic profiling across multiple experimental systems—including postmortem human brain tissue, patient-derived neural progenitor cells (NPCs), neurons, and cerebral organoids—reveals consistently elevated expression of histone variants H1.2 and H1.5 in idiopathic ASD and in 16p11.2 CNV carriers with ASD or SCZ, but not in idiopathic SCZ or bipolar disorder. Functional assays demonstrate that dysregulated H1 expression disrupts networks involved in synaptic signalling, chromatin remodelling, and neural differentiation. Using a deep learning framework incorporating Variational Autoencoder (VAE) and SHAP-based feature importance, we uncover distinct regulatory pathways driven by H1 overexpression. Notably, this overexpression induces bidirectional transcriptional changes within the 16p11.2 locus, mirroring expression signatures of both deletions and duplications. Our findings establish H1.2 and H1.5 as key regulators of transcriptional programs in neurodevelopmental disorders, highlighting chromatin-mediated mechanisms underlying ASD and SCZ and their potential as biomarkers. Overall design: Comparative gene expression analysis of RNA-seq data for WT SH-SY5Y and its KD and OE