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

• Published in: Nature neuroscience Vol. 25; no. 4; pp. 474 - 483
• Main Authors: Girdhar, Kiran, Hoffman, Gabriel E., Bendl, Jaroslav, Rahman, Samir, Dong, Pengfei, Liao, Will, Hauberg, Mads E., Sloofman, Laura, Brown, Leanne, Devillers, Olivia, Kassim, Bibi S., Wiseman, Jennifer R., Park, Royce, Zharovsky, Elizabeth, Jacobov, Rivky, Flatow, Elie, Kozlenkov, Alexey, Gilgenast, Thomas, Johnson, Jessica S., Couto, Lizette, Peters, Mette A., Phillips-Cremins, Jennifer E., Hahn, Chang-Gyu, Gur, Raquel E., Tamminga, Carol A., Lewis, David A., Haroutunian, Vahram, Dracheva, Stella, Lipska, Barbara K., Marenco, Stefano, Kundakovic, Marija, Fullard, John F., Jiang, Yan, Roussos, Panos, Akbarian, Schahram
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2022; Nature Publishing Group
• Subjects: 631/114/1314; 631/208/177; 631/378/1689/1333; 692/699/476/1799; Acetylation; Adult; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Bipolar disorder; Bipolar Disorder - genetics; Brain; Chromatin; Domains; Fetuses; Gene mapping; Glutamatergic transmission; Heritability; Histones; Humans; Lysine; Lysine - genetics; Mental disorders; Methylation; Neurobiology; Neurosciences; Prefrontal cortex; Regulatory sequences; Schizophrenia; Schizophrenia - genetics; Transcription
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-022-01032-6

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, 10 4 –10 6 -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. Girdhar et al. constructed chromosomal domains from prefrontal histone acetylation and methylation maps and discovered, in a large cohort of schizophrenia and bipolar brains, converging alignment by genetic risk, neuronal function and three-dimensional genomics.