Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains

Chromosomal organization, scaling from the 147 base pair nucleosome to megabase-ranging domains encompassing multiple transcriptional units including heritability loci for psychiatric traits, remains largely unexplored in the human brain. Here, we construct promoter and enhancer enriched nucleosomal histone modification landscapes for adult prefrontal cortex (PFC) from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from (n=739) 388 controls and 351 subjects diagnosed with schizophrenia (SCZ) or bipolar disorder (BD). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 10(4)-10(6) bp chromosomal organization, firmly integrated into Hi-C topologically associating domain (TAD) stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyperacetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilo- to megabase-scaling chromosomal domains.