Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons
| Autor: | John F. Fullard, Mads E. Hauberg, Sarah Chowdhury, Stella Dracheva, Michael Wegner, Jaroslav Bendl, Chuhyon Corwin, Panos Roussos, Alexey Kozlenkov, Biao Zeng, Yasmin L. Hurd, Anders D. Børglum, Jordi Creus-Muncunill, Harald Kranz, Michelle E. Ehrlich |
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| Rok vydání: | 2020 |
| Předmět: |
Epigenomics
0301 basic medicine General Physics and Astronomy Epigenesis Genetic Mice 0302 clinical medicine Risk Factors Epigenetics and behaviour GABAergic Neurons lcsh:Science Promoter Regions Genetic Visual Cortex Neurons Multidisciplinary Human brain Chromatin Oligodendroglia medicine.anatomical_structure RNA Long Noncoding Microglia Clinical epigenetics Cell type Science Prefrontal Cortex Mice Transgenic Biology Gyrus Cinguli Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Glutamatergic medicine Animals Humans Transcription factor General Chemistry Epigenome Dorsolateral prefrontal cortex MicroRNAs 030104 developmental biology Visual cortex Gene Expression Regulation Astrocytes Schizophrenia lcsh:Q Neuroscience 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Nature Communications Hauberg, M E, Creus-Muncunill, J, Bendl, J, Kozlenkov, A, Zeng, B, Corwin, C, Chowdhury, S, Kranz, H, Hurd, Y L, Wegner, M, Børglum, A D, Dracheva, S, Ehrlich, M E, Fullard, J F & Roussos, P 2020, ' Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons ', Nature Communications, vol. 11, 5581 . https://doi.org/10.1038/s41467-020-19319-2 Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) |
| ISSN: | 2041-1723 |
| Popis: | 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. Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits. |
| Databáze: | OpenAIRE |
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