Decoupling of evolutionary changes in transcription factor binding and gene expression in mammals.
To understand the evolutionary dynamics between transcription factor (TF) binding and gene expression in mammals, we compared transcriptional output and the binding intensities for three tissue-specific TFs in livers from four closely related mouse species. For each transcription factor, TF-dependent genes and the TF binding sites most likely to influence mRNA expression were identified by comparing mRNA expression levels between wild-type and TF knockout mice. Independent evolution was observed genome-wide between the rate of change in TF binding and the rate of change in mRNA expression across taxa, with the exception of a small number of TF-dependent genes. We also found that binding intensities are preferentially conserved near genes whose expression is dependent on the TF, and the conservation is shared among binding peaks in close proximity to each other near the TSS. Expression of TF-dependent genes typically showed an increased sensitivity to changes in binding levels as measured by mRNA abundance. Taken together, these results highlight a significant tolerance to evolutionary changes in TF binding intensity in mammalian transcriptional networks and suggest that some TF-dependent genes may be largely regulated by a single TF across evolution.
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom;
Emily S
http://orcid.org/0000-0003-0315-2942
ES
Wong
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom;
David
http://orcid.org/0000-0001-7806-7318
D
Thybert
University of Cambridge, Cancer Research UK - Cambridge Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, United Kingdom;
Bianca M
BM
Schmitt
University of Cambridge, Cancer Research UK - Cambridge Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, United Kingdom;
Klara
K
Stefflova
University of Cambridge, Cancer Research UK - Cambridge Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom duncan.odom@cruk.cam.ac.uk flicek@ebi.ac.uk.
Duncan T
DT
Odom
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom duncan.odom@cruk.cam.ac.uk flicek@ebi.ac.uk.
Paul
http://orcid.org/0000-0002-3897-7955
P
Flicek
D000818:Animals; D001665:Binding Sites; D005075:Biological Evolution; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D014644:Genetic Variation; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D008322:Mammals / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015233:Models, Statistical; D011485:Protein Binding; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D014157:Transcription Factors