Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci.
Open chromatin provides access to DNA-binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease. To better understand the role of CREs in neuropsychiatric disorders we applied the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) to neuronal and non-neuronal nuclei isolated from frozen postmortem human brain by fluorescence-activated nuclear sorting (FANS). Most of the identified open chromatin regions (OCRs) are differentially accessible between neurons and non-neurons, and show enrichment with known cell type markers, promoters and enhancers. Relative to those of non-neurons, neuronal OCRs are more evolutionarily conserved and are enriched in distal regulatory elements. Transcription factor (TF) footprinting analysis identifies differences in the regulome between neuronal and non-neuronal cells and ascribes putative functional roles to a number of non-coding schizophrenia (SCZ) risk variants. Among the identified variants is a Single Nucleotide Polymorphism (SNP) proximal to the gene encoding SNX19. In vitro experiments reveal that this SNP leads to an increase in transcriptional activity. As elevated expression of SNX19 has been associated with SCZ, our data provide evidence that the identified SNP contributes to disease. These results represent the first analysis of OCRs and TF-binding sites in distinct populations of postmortem human brain cells and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
John F
JF
Fullard
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Claudia
C
Giambartolomei
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Department of Biomedicine.|Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Denmark.
Mads E
ME
Hauberg
Department of Genetics and Genomic Science and Institute for Multiscale Biology.
Ke
K
Xu
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Georgios
G
Voloudakis
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Department of Neuroscience.|Center for Molecular Biology and Genetics of Neurodegeneration.
Zhiping
Z
Shao
Flow Cytometry Center of Research Excellence, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Christopher
C
Bare
Department of Genetics and Genomic Science and Institute for Multiscale Biology.
Joel T
JT
Dudley
Department of Biomedicine.|Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Denmark.
Manuel
M
Mattheisen
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Department of Neuroscience.|Center for Molecular Biology and Genetics of Neurodegeneration.
Nikolaos K
NK
Robakis
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Department of Neuroscience.|Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, USA.
Vahram
V
Haroutunian
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Department of Genetics and Genomic Science and Institute for Multiscale Biology.|Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, USA.
Panos
P
Roussos
D001921:Brain / Q000378:metabolism; D001931:Brain Mapping / Q000379:methods; D002843:Chromatin / Q000378:metabolism / Q000473:pathology*; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics* / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D058305:Sorting Nexins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D002843:Chromatin; D004268:DNA-Binding Proteins; D058305:Sorting Nexins; D014157:Transcription Factors