TY - JOUR
T1 - An atlas of chromatin accessibility in the adult human brain
AU - Fullard, John F.
AU - Hauberg, Mads E.
AU - Bendl, Jaroslav
AU - Egervari, Gabor
AU - Cirnaru, Maria Daniela
AU - Reach, Sarah M.
AU - Motl, Jan
AU - Ehrlich, Michelle E.
AU - Hurd, Yasmin L.
AU - Roussos, Panos
N1 - Funding Information:
Data on coronary artery disease/myocardial infarction have been contributed by CARDIoGRAMplusC4D investigators. We additionally thank the International Genomics of Alzheimer’s Project (IGAP) for providing GWAS summary results. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. Next-generation sequencing was performed at the New York Genome Center. FANS was performed at the Mount Sinai Flow Cytometry CoRE, and mouse transgenics were performed at the Mount Sinai Mouse Genetics CoRE facility. This work was supported by the National Institutes of Health (National Institute on Aging, R01AG050986 to P.R.; National Institute of Mental Health, R01MH109677 to P.R.; National Institute of Neurological Disorders and Stroke, R01NS100529 to M.E.E.; and National Institute on Drug Abuse, R01DA015446 to Y.L.H.), Brain Behavior Research Foundation (National Alliance for Research on Schizophrenia and Depression, 20540 to P.R.), Alzheimer’s Association (NIRG-340998 to P.R.), New York State Stem Cell Science (N13G-169 to M.E.E.), and the Veterans Affairs (Merit Grant BX002395 to P.R.). This study was additionally funded by The Lundbeck Foundation, Denmark (Grant No. R102-A9118). Further, this work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Publisher Copyright:
© 2018 Fullard et al.
PY - 2018/8
Y1 - 2018/8
N2 - Most common genetic risk variants associated with neuropsychiatric disease are noncoding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type-specific open chromatin data set to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in two cell types (neurons and non-neurons) across 14 distinct brain regions of five individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein-coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provide a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database “Brain Open Chromatin Atlas (BOCA)” to facilitate interpretation.
AB - Most common genetic risk variants associated with neuropsychiatric disease are noncoding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type-specific open chromatin data set to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in two cell types (neurons and non-neurons) across 14 distinct brain regions of five individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein-coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provide a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database “Brain Open Chromatin Atlas (BOCA)” to facilitate interpretation.
UR - http://www.scopus.com/inward/record.url?scp=85050870595&partnerID=8YFLogxK
U2 - 10.1101/gr.232488.117
DO - 10.1101/gr.232488.117
M3 - Article
C2 - 29945882
AN - SCOPUS:85050870595
SN - 1088-9051
VL - 28
SP - 1243
EP - 1252
JO - Genome research
JF - Genome research
IS - 8
ER -