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Brain cell type-specific enhancer-promoter interactome maps and disease-risk association.

ABSTRACT: Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

SUBMITTER: Nott A

PROVIDER: S-EPMC7028213 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Brain cell type-specific enhancer-promoter interactome maps and disease<b>-</b>risk association.

Nott Alexi A Holtman Inge R IR Coufal Nicole G NG Schlachetzki Johannes C M JCM Yu Miao M Hu Rong R Han Claudia Z CZ Pena Monique M Xiao Jiayang J Wu Yin Y Keulen Zahara Z Pasillas Martina P MP O'Connor Carolyn C Nickl Christian K CK Schafer Simon T ST Shen Zeyang Z Rissman Robert A RA Brewer James B JB Gosselin David D Gonda David D DD Levy Michael L ML Rosenfeld Michael G MG McVicker Graham G Gage Fred H FH Ren Bing B Glass Christopher K CK

Science (New York, N.Y.) 20191114 6469

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactom ...[more]

PMID: 31727856

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Project description:In multicellular organisms, transcription regulation is one of the central mechanisms modelling lineage differentiation and cell-fate determination. Transcription requires dynamic chromatin configurations between promoters and their corresponding distal regulatory elements. It is believed that their communication occurs within large discrete foci of aggregated RNA polymerases termed transcription factories in three-dimensional nuclear space. However, the dynamic nature of chromatin connectivity has not been characterized at the genome-wide level. Here, through a chromatin interaction analysis with paired-end tagging approach using an antibody that primarily recognizes the pre-initiation complexes of RNA polymerase II, we explore the transcriptional interactomes of three mouse cells of progressive lineage commitment, including pluripotent embryonic stem cells, neural stem cells and neurosphere stem/progenitor cells. Our global chromatin connectivity maps reveal approximately 40,000 long-range interactions, suggest precise enhancer-promoter associations and delineate cell-type-specific chromatin structures. Analysis of the complex regulatory repertoire shows that there are extensive colocalizations among promoters and distal-acting enhancers. Most of the enhancers associate with promoters located beyond their nearest active genes, indicating that the linear juxtaposition is not the only guiding principle driving enhancer target selection. Although promoter-enhancer interactions exhibit high cell-type specificity, promoters involved in interactions are found to be generally common and mostly active among different cells. Chromatin connectivity networks reveal that the pivotal genes of reprogramming functions are transcribed within physical proximity to each other in embryonic stem cells, linking chromatin architecture to coordinated gene expression. Our study sets the stage for the full-scale dissection of spatial and temporal genome structures and their roles in orchestrating development.

Dataset Information

Brain cell type-specific enhancer-promoter interactome maps and disease-risk association.

Publications

Brain cell type-specific enhancer-promoter interactome maps and disease<b>-</b>risk association.

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