An atlas of chromatin accessibility in the adult human brain

Author:

Fullard John F.ORCID,Hauberg Mads E.ORCID,Bendl JaroslavORCID,Egervari GaborORCID,Cirnaru Maria-DanielaORCID,Reach Sarah M.,Motl Jan,Ehrlich Michelle E.ORCID,Hurd Yasmin L.ORCID,Roussos PanosORCID

Abstract

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.

Funder

French National Foundation on Alzheimer's disease and related disorders

LABEX

DISTALZ

Inserm

Medical Research Council

Alzheimer's Research UK

Wellcome Trust

German Federal Ministry of Education and Research

Competence Network Dementia

NIH

NIA

AGES

NHLBI

Icelandic Heart Association

Erasmus Medical Center

Erasmus University

Alzheimer's Association

National Institutes of Health

National Institute on Aging

National Institute of Mental Health

National Institute of Neurological Disorders and Stroke

Brain Behavior Research Foundation

National Alliance for Research on Schizophrenia and Depression

New York State Stem Cell Science

Veterans Affairs

The Lundbeck Foundation, Denmark

Publisher

Cold Spring Harbor Laboratory

Subject

Genetics(clinical),Genetics

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