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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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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. |
format | Online Article Text |
id | pubmed-10333863 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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