Transcription factor expression is the main determinant of variability in gene co-activity
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Transcription factor expression is the main determinant of variability in gene co-activity. / van Duin, Lucas; Krautz, Robert; Rennie, Sarah; Andersson, Robin.
In: Molecular Systems Biology, Vol. 19, No. 7, e11392, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Transcription factor expression is the main determinant of variability in gene co-activity
AU - van Duin, Lucas
AU - Krautz, Robert
AU - Rennie, Sarah
AU - Andersson, Robin
N1 - Publisher Copyright: © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - co-activity domains
KW - co-regulation
KW - gene regulation
KW - individual variation
KW - transcriptional decomposition
U2 - 10.15252/msb.202211392
DO - 10.15252/msb.202211392
M3 - Journal article
C2 - 37158788
AN - SCOPUS:85158830433
VL - 19
JO - Molecular Systems Biology
JF - Molecular Systems Biology
SN - 1744-4292
IS - 7
M1 - e11392
ER -
ID: 370684395