Binary outcomes of enhancer activity underlie stable random monoallelic expression
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 enhance...
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eLife Sciences Publications Ltd
2022-05-01
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Online Access: | https://elifesciences.org/articles/74204 |
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author | Djem U Kissiov Alexander Ethell Sean Chen Natalie K Wolf Chenyu Zhang Susanna M Dang Yeara Jo Katrine N Madsen Ishan Paranjpe Angus Y Lee Bryan Chim Stefan A Muljo David H Raulet |
author_facet | Djem U Kissiov Alexander Ethell Sean Chen Natalie K Wolf Chenyu Zhang Susanna M Dang Yeara Jo Katrine N Madsen Ishan Paranjpe Angus Y Lee Bryan Chim Stefan A Muljo David H Raulet |
author_sort | Djem U Kissiov |
collection | DOAJ |
description | 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. |
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language | English |
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spelling | doaj.art-9505cd27acaf469ab8f89ecc6921b8c02022-12-22T03:50:54ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.74204Binary outcomes of enhancer activity underlie stable random monoallelic expressionDjem U Kissiov0https://orcid.org/0000-0001-6279-342XAlexander Ethell1Sean Chen2Natalie K Wolf3Chenyu Zhang4Susanna M Dang5Yeara Jo6Katrine N Madsen7Ishan Paranjpe8Angus Y Lee9Bryan Chim10Stefan A Muljo11David H Raulet12https://orcid.org/0000-0002-1257-8649Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesCancer Research Laboratory, University of California, Berkeley, Berkeley, United StatesLaboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United StatesLaboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesMitotically 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.https://elifesciences.org/articles/74204Monoallelicgene regulationLy49NKG2DEnhancer |
spellingShingle | Djem U Kissiov Alexander Ethell Sean Chen Natalie K Wolf Chenyu Zhang Susanna M Dang Yeara Jo Katrine N Madsen Ishan Paranjpe Angus Y Lee Bryan Chim Stefan A Muljo David H Raulet Binary outcomes of enhancer activity underlie stable random monoallelic expression eLife Monoallelic gene regulation Ly49 NKG2D Enhancer |
title | Binary outcomes of enhancer activity underlie stable random monoallelic expression |
title_full | Binary outcomes of enhancer activity underlie stable random monoallelic expression |
title_fullStr | Binary outcomes of enhancer activity underlie stable random monoallelic expression |
title_full_unstemmed | Binary outcomes of enhancer activity underlie stable random monoallelic expression |
title_short | Binary outcomes of enhancer activity underlie stable random monoallelic expression |
title_sort | binary outcomes of enhancer activity underlie stable random monoallelic expression |
topic | Monoallelic gene regulation Ly49 NKG2D Enhancer |
url | https://elifesciences.org/articles/74204 |
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