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Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletion...

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Autores principales: Hoeksema, Marten A., Shen, Zeyang, Holtman, Inge R., Zheng, An, Spann, Nathan J., Cobo, Isidoro, Gymrek, Melissa, Glass, Christopher K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208725/
https://www.ncbi.nlm.nih.gov/pubmed/34134993
http://dx.doi.org/10.1126/sciadv.abf9808
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author Hoeksema, Marten A.
Shen, Zeyang
Holtman, Inge R.
Zheng, An
Spann, Nathan J.
Cobo, Isidoro
Gymrek, Melissa
Glass, Christopher K.
author_facet Hoeksema, Marten A.
Shen, Zeyang
Holtman, Inge R.
Zheng, An
Spann, Nathan J.
Cobo, Isidoro
Gymrek, Melissa
Glass, Christopher K.
author_sort Hoeksema, Marten A.
collection PubMed
description Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletions provided by five inbred strains of mice on the responses of macrophages to interleukin-4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage-determining and signal-dependent transcription factors driving IL-4 enhancer activation. These studies further revealed mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.
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spelling pubmed-82087252021-06-28 Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4 Hoeksema, Marten A. Shen, Zeyang Holtman, Inge R. Zheng, An Spann, Nathan J. Cobo, Isidoro Gymrek, Melissa Glass, Christopher K. Sci Adv Research Articles Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletions provided by five inbred strains of mice on the responses of macrophages to interleukin-4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage-determining and signal-dependent transcription factors driving IL-4 enhancer activation. These studies further revealed mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity. American Association for the Advancement of Science 2021-06-16 /pmc/articles/PMC8208725/ /pubmed/34134993 http://dx.doi.org/10.1126/sciadv.abf9808 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Hoeksema, Marten A.
Shen, Zeyang
Holtman, Inge R.
Zheng, An
Spann, Nathan J.
Cobo, Isidoro
Gymrek, Melissa
Glass, Christopher K.
Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4
title Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4
title_full Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4
title_fullStr Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4
title_full_unstemmed Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4
title_short Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4
title_sort mechanisms underlying divergent responses of genetically distinct macrophages to il-4
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208725/
https://www.ncbi.nlm.nih.gov/pubmed/34134993
http://dx.doi.org/10.1126/sciadv.abf9808
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