Binary outcomes of enhancer activity underlie stable random monoallelic expression
| Autor: | Djem U. Kissiov, Alexander Ethell, Sean Chen, Natalie K. Wolf, Chenyu Zhang, Susanna M. Dang, Yeara Jo, Katrine N. Madsen, Ishan D. Paranjpe, Angus Y. Lee, Bryan Chim, Stefan A. Muljo, David H. Raulet |
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| Rok vydání: | 2022 |
| Předmět: |
chromosomes
Enhancer Elements Mouse 1.1 Normal biological development and functioning Biology Regulatory Sequences Nucleic Acid Ly49 General Biochemistry Genetics and Molecular Biology Chromosomes NKG2D immunology Mice Genetic Underpinning research Gene expression Genetics Animals Allele Enhancer Receptor Gene Monoallelic Alleles Variegation General Immunology and Microbiology Nucleic Acid General Neuroscience General Medicine CD8A Enhancer Elements Genetic Gene Expression Regulation NK Cell Lectin-Like Receptor Subfamily K inflammation gene expression Biochemistry and Cell Biology gene regulation Regulatory Sequences Biotechnology |
| Popis: | Mitotically stable random monoallelic gene expression (RME) is documented for a small percentage of autosomal genes. We developed an in vivo genetic model to study the role of enhancers in RME using high-resolution single-cell analysis of natural killer (NK) cell receptor gene expression and enhancer deletions in the mouse germline. Enhancers of the RME NK receptor genes were accessible and enriched in H3K27ac on silent and active alleles alike in cells sorted according to allelic expression status, suggesting enhancer activation and gene expression status can be decoupled. In genes with multiple enhancers, enhancer deletion reduced gene expression frequency, in one instance converting the universally expressed gene encoding NKG2D into an RME gene, recapitulating all aspects of natural RME including mitotic stability of both the active and silent states. The results support the binary model of enhancer action, and suggest that RME is a consequence of general properties of gene regulation by enhancers rather than an RME-specific epigenetic program. Therefore, many and perhaps all genes may be subject to some degree of RME. Surprisingly, this was borne out by analysis of several genes that define different major hematopoietic lineages, that were previously thought to be universally expressed within those lineages: the genes encoding NKG2D, CD45, CD8α, and Thy-1. We propose that intrinsically probabilistic gene allele regulation is a general property of enhancer-controlled gene expression, with previously documented RME representing an extreme on a broad continuum. |
| Databáze: | OpenAIRE |
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