Brain cell type-specific enhancer-promoter interactome maps and disease risk association
By A. Nott, I. Holtman, Nicole G. Coufal, J. Schlachetzki, Miao Yu, Rong Hu, Claudia Z. Han, Monique Pena, Jiayang Xiao, Yin Wu and 16 more. Science, 2019
654 citations recorded by the source corpus.
Linking enhancers to disease Enhancers are genomic regions that regulate gene expression, sometimes in a cell-dependent manner. However, most of our knowledge of human brain cell–type enhancers derives from studies of bulk human brain tissue. Nott et al. examined chromatin and promoter activity in cell nuclei isolated from human brains. Genetic variants associated with brain traits and disease showed cell-specific patterns of enhancer enrichment. These data indicate that Alzheimer's disease is regulated by genetic variants within microglial cells, whereas psychiatric diseases tend to affect neurons. Science, this issue p. 1134 Cell type–specific regulatory elements in the human brain reveal noncoding variants associated with neurological diseases. 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.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/7a5a15720dccbd1ffaefb1a3e7b92e9e1219a946
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In Molecular Biology
Citations in the corpus
- Astrocyte crosstalk in CNS inflammation (2020, background): “Indeed, it has been recently reported that microglia can also undergo training (Nott and Glass, 2018; Nott et al., 2019; Wendeln et al., 2018).”