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Transcription factor expression is the main determinant of variability in gene co‐activity

Many genes are co‐expressed and form genomic domains of coordinated gene activity. However, the regulatory determinants of domain co‐activity remain unclear. Here, we leverage human individual variation in gene expression to characterize the co‐regulatory processes underlying domain co‐activity and...

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Autores principales: van Duin, Lucas, Krautz, Robert, Rennie, Sarah, Andersson, Robin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333863/
https://www.ncbi.nlm.nih.gov/pubmed/37158788
http://dx.doi.org/10.15252/msb.202211392
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author van Duin, Lucas
Krautz, Robert
Rennie, Sarah
Andersson, Robin
author_facet van Duin, Lucas
Krautz, Robert
Rennie, Sarah
Andersson, Robin
author_sort van Duin, Lucas
collection PubMed
description Many genes are co‐expressed and form genomic domains of coordinated gene activity. However, the regulatory determinants of domain co‐activity remain unclear. Here, we leverage human individual variation in gene expression to characterize the co‐regulatory processes underlying domain co‐activity and systematically quantify their effect sizes. We employ transcriptional decomposition to extract from RNA expression data an expression component related to co‐activity revealed by genomic positioning. This strategy reveals close to 1,500 co‐activity domains, covering most expressed genes, of which the large majority are invariable across individuals. Focusing specifically on domains with high variability in co‐activity reveals that contained genes have a higher sharing of eQTLs, a higher variability in enhancer interactions, and an enrichment of binding by variably expressed transcription factors, compared to genes within non‐variable domains. Through careful quantification of the relative contributions of regulatory processes underlying co‐activity, we find transcription factor expression levels to be the main determinant of gene co‐activity. Our results indicate that distal trans effects contribute more than local genetic variation to individual variation in co‐activity domains.
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spelling pubmed-103338632023-07-12 Transcription factor expression is the main determinant of variability in gene co‐activity van Duin, Lucas Krautz, Robert Rennie, Sarah Andersson, Robin Mol Syst Biol Articles Many genes are co‐expressed and form genomic domains of coordinated gene activity. However, the regulatory determinants of domain co‐activity remain unclear. Here, we leverage human individual variation in gene expression to characterize the co‐regulatory processes underlying domain co‐activity and systematically quantify their effect sizes. We employ transcriptional decomposition to extract from RNA expression data an expression component related to co‐activity revealed by genomic positioning. This strategy reveals close to 1,500 co‐activity domains, covering most expressed genes, of which the large majority are invariable across individuals. Focusing specifically on domains with high variability in co‐activity reveals that contained genes have a higher sharing of eQTLs, a higher variability in enhancer interactions, and an enrichment of binding by variably expressed transcription factors, compared to genes within non‐variable domains. Through careful quantification of the relative contributions of regulatory processes underlying co‐activity, we find transcription factor expression levels to be the main determinant of gene co‐activity. Our results indicate that distal trans effects contribute more than local genetic variation to individual variation in co‐activity domains. John Wiley and Sons Inc. 2023-05-09 /pmc/articles/PMC10333863/ /pubmed/37158788 http://dx.doi.org/10.15252/msb.202211392 Text en © 2023 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
van Duin, Lucas
Krautz, Robert
Rennie, Sarah
Andersson, Robin
Transcription factor expression is the main determinant of variability in gene co‐activity
title Transcription factor expression is the main determinant of variability in gene co‐activity
title_full Transcription factor expression is the main determinant of variability in gene co‐activity
title_fullStr Transcription factor expression is the main determinant of variability in gene co‐activity
title_full_unstemmed Transcription factor expression is the main determinant of variability in gene co‐activity
title_short Transcription factor expression is the main determinant of variability in gene co‐activity
title_sort transcription factor expression is the main determinant of variability in gene co‐activity
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333863/
https://www.ncbi.nlm.nih.gov/pubmed/37158788
http://dx.doi.org/10.15252/msb.202211392
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