Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders
Benxia Hu(University of North Carolina at Chapel Hill), Hyejung Won(University of North Carolina at Chapel Hill), Won Mah(University of North Carolina at Chapel Hill), Royce Park(Allen Institute for Brain Science), Bibi Kassim(Allen Institute for Brain Science), Keeley Spiess(University of North Carolina at Chapel Hill), Alexey Kozlenkov(Allen Institute for Brain Science), Cheynna Crowley(University of North Carolina at Chapel Hill), Sirisha Pochareddy, Allison E. Ashley‐Koch(Duke University), Gregory E. Crawford(Duke University), Melanie E. Garrett(Duke University), Lingyun Song(Duke University), Alexias Safi(Duke University), Graham D. Johnson(Duke University), Gregory A. Wray(Duke University), Timothy E. Reddy(Duke University), Fernando S. Goes(Johns Hopkins University), Peter P. Zandi(Johns Hopkins University), Julien Bryois(Karolinska Institutet), Andrew E. Jaffe(Lieber Institute for Brain Development), Amanda J. Price(Lieber Institute for Brain Development), Nikolay A. Ivanov(Lieber Institute for Brain Development), Leonardo Collado‐Torres(Lieber Institute for Brain Development), Thomas M. Hyde(Lieber Institute for Brain Development), Emily E. Burke(Lieber Institute for Brain Development), Joel E. Kleiman(Lieber Institute for Brain Development), Ran Tao(Lieber Institute for Brain Development), Joo Heon Shin(Lieber Institute for Brain Development), Kiran Girdhar(Allen Institute for Brain Science), Yan Jiang(Allen Institute for Brain Science), Marija Kundaković(Allen Institute for Brain Science), Leanne Brown(Allen Institute for Brain Science), Jennifer Wiseman(Allen Institute for Brain Science), Elizabeth Zharovsky(Allen Institute for Brain Science), Rivka Jacobov(Allen Institute for Brain Science), Olivia Devillers(Allen Institute for Brain Science), Elie Flatow(Allen Institute for Brain Science), Gabriel E. Hoffman(Allen Institute for Brain Science), Judson Belmont(Allen Institute for Brain Science), Diane M. Del Valle(Allen Institute for Brain Science), Nancy Francoeur(Allen Institute for Brain Science), Evi Hadjimichael(Allen Institute for Brain Science), Dalila Pinto(Allen Institute for Brain Science), Harm van Bakel(Allen Institute for Brain Science), Panos Roussos(Allen Institute for Brain Science), John F. Fullard(Allen Institute for Brain Science), Jaroslav Bendl(Allen Institute for Brain Science), Mads E. Hauberg(Allen Institute for Brain Science), Alexander W. Charney(Allen Institute for Brain Science), Vahram Haroutunian(James J. Peters VA Medical Center), Barbara K. Lipska(National Institutes of Health), David A. Lewis(University of Pittsburgh), Chang-Gyu Hahn(University of Pennsylvania), Lara M. Mangravite(Sage Bionetworks), Mette A. Peters(Sage Bionetworks), Yooree Chae(Sage Bionetworks), Junmin Peng(St. Jude Children's Research Hospital), Mingming Niu(St. Jude Children's Research Hospital), Xusheng Wang(St. Jude Children's Research Hospital), Maree J. Webster(Stanley Medical Research Institute), Thomas G. Beach(Banner Sun Health Research Institute), Chao Chen(Central South University), Yi Jiang(Allen Institute for Brain Science), Rujia Dai(Central South University), Yongjun Wang(Central South University), Yan Xia(Central South University), Annie W. Shieh(SUNY Upstate Medical University), Chunyu Liu(SUNY Upstate Medical University), Kay Grennan(SUNY Upstate Medical University), Ramu Vadukapuram(SUNY Upstate Medical University), Gina Giase(SUNY Upstate Medical University), Dominic Fitzgerald(University of Chicago), Lijun Cheng(University of Chicago), Miguel Brown(University of Chicago), Mimi Brown(University of Chicago), Tonya M. Brunetti(University of Chicago), Thomas Goodman(University of Chicago), Majd Alsayed(University of Chicago), Kevin P. White(University of Chicago), Mohana Ray(University of Chicago), Damon Polioudakis(University of California, Los Angeles), Brie Wamsley(University of California, Los Angeles), Jiani Yin(University of California, Los Angeles), Luis de la Torre-Ubieta(University of California, Los Angeles), Michael J. Gandal(University of California, Los Angeles), Vivek Swarup(University of California, Los Angeles), Stephan Sanders(University of California, San Francisco), Matthew W. State(University of California, San Francisco), Donna M. Werling(University of California, San Francisco), Joon‐Yong An(University of California, San Francisco), Brooke Sheppard(University of California, San Francisco), A. Jeremy Willsey(University of California, San Francisco), Amira Kefi(University of Illinois Chicago), Eugenio Mattei(University of Massachusetts Chan Medical School), Michael Purcaro(University of Massachusetts Chan Medical School), Zhiping Weng(University of Massachusetts Chan Medical School), J. Russell Moore(University of Massachusetts Chan Medical School), Henry Pratt(University of Massachusetts Chan Medical School), Jack Huey(University of Massachusetts Chan Medical School), Tyler Borrman(University of Massachusetts Chan Medical School), Patrick F. Sullivan(University of North Carolina at Chapel Hill), Paola Giusti‐Rodríguez(University of North Carolina at Chapel Hill), Yunjung Kim(University of North Carolina at Chapel Hill), Jin Szatkiewicz(University of North Carolina at Chapel Hill), Suhn K. Rhie(University of Southern California), Christoper Armoskus(University of Southern California), Adrian Camarena(University of Southern California), Peggy Farnham(University of Southern California), Valeria N. Spitsyna(University of Southern California), Heather Witt(University of Southern California), Shannon Schreiner(University of Southern California), Oleg V. Evgrafov(SUNY Downstate Health Sciences University), James A. Knowles(SUNY Downstate Health Sciences University), Mark Gerstein(Yale University), Shuang Liu(Yale University), Fábio C. P. Navarro(Yale University), Jonathan Warrell(Yale University), Declan Clarke(Yale University), Prashant S. Emani(Yale University), Mengting Gu(Yale University), Xu Shi(Yale University), Min Xu(Yale University), Yucheng Yang(Yale University), Robert R. Kitchen(Yale University), Gamze Gürsoy(Yale University), Jing Zhang(Yale University), Becky C. Carlyle, Angus C. Nairn, Mingfeng Li, Mario Škarica, Zhen Li, André M. M. Sousa, Gabriel Santpere, Jinmyung Choi, Ying Zhu, Tianliuyun Gao, Daniel J. Miller, Adriana Cherskov, Mo Yang, Anahita Amiri, Gianfilippo Coppola, Jessica Mariani, Soraya Scuderi, Anna Szekely, Flora M. Vaccarino, Feinan Wu, Sherman M. Weissman, Daifeng Wang(University of Wisconsin–Madison), Tanmoy Roychowdhury(Mayo Clinic), Alexej Abyzov(Mayo Clinic), Yun Li(University of North Carolina at Chapel Hill), Stella Dracheva(Allen Institute for Brain Science), Nenad Šestan(Yale University), Schahram Akbarian(Allen Institute for Brain Science), Daniel H. Geschwind(University of California, Los Angeles)
Cited by 107Open Access
Abstract
Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer's disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.
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