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

PsychENCODE Consortium

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104–106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated 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 kilobase- to megabase-scaling chromosomal domains.

Original languageEnglish (US)
Pages (from-to)474-483
Number of pages10
JournalNature neuroscience
Volume25
Issue number4
DOIs
StatePublished - Apr 2022
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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