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Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons.
- Source :
-
Nature communications [Nat Commun] 2020 Nov 04; Vol. 11 (1), pp. 5581. Date of Electronic Publication: 2020 Nov 04. - Publication Year :
- 2020
-
Abstract
- The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability. Transcription factor footprinting implicates cell-specific transcriptional regulators and infers cell-specific regulation of protein-coding genes, long intergenic noncoding RNAs and microRNAs. In vivo transgenic mouse experiments validate the cell type specificity of several of these human-derived regulatory sequences. We find that open chromatin regions in glutamatergic neurons are enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Integration of cell-specific chromatin data with a bulk tissue study of schizophrenia brains increases statistical power and confirms that glutamatergic neurons are most affected. These findings illustrate the utility of studying the cell-type-specific epigenome in complex tissues like the human brain, and the potential of such approaches to better understand the genetic basis of human brain function.
- Subjects :
- Animals
Chromatin genetics
Epigenesis, Genetic
Gene Expression Regulation genetics
Gyrus Cinguli cytology
Gyrus Cinguli metabolism
Humans
Mice
Mice, Transgenic
MicroRNAs metabolism
Prefrontal Cortex cytology
Prefrontal Cortex metabolism
Promoter Regions, Genetic
RNA, Long Noncoding metabolism
Risk Factors
Schizophrenia genetics
Transcription Factors metabolism
Visual Cortex cytology
Visual Cortex metabolism
Astrocytes metabolism
Chromatin metabolism
GABAergic Neurons metabolism
Microglia metabolism
Neurons metabolism
Oligodendroglia metabolism
Schizophrenia metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33149216
- Full Text :
- https://doi.org/10.1038/s41467-020-19319-2