Cooperativity and Rapid Evolution of Cobound Transcription Factors in Closely Related Mammals

Summary

To mechanistically characterize the microevolutionary processes active in altering transcription factor (TF) binding among closely related mammals, we compared the genome-wide binding of three tissue-specific TFs that control liver gene expression in six rodents. Despite an overall fast turnover of TF binding locations between species, we identified thousands of TF regions of highly constrained TF binding intensity. Although individual mutations in bound sequence motifs can influence TF binding, most binding differences occur in the absence of nearby sequence variations. Instead, combinatorial binding was found to be significant for genetic and evolutionary stability; cobound TFs tend to disappear in concert and were sensitive to genetic knockout of partner TFs. The large, qualitative differences in genomic regions bound between closely related mammals, when contrasted with the smaller, quantitative TF binding differences among Drosophila species, illustrate how genome structure and population genetics together shape regulatory evolution.

Graphical Abstract

Highlights

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  Earliest steps of regulatory evolution in mammals captured using five mouse species

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  Interspecies differences in TF binding are rarely caused by DNA variation in motifs

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  Cobound TFs change their genomic binding cooperatively in closely related mammals

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  Genetic knockouts revealed the extent of cooperative stabilization in TF binding clusters

Abstract

Microevolutionary mechanisms create different transcription factor binding patterns between mammals, shedding light on the regulatory mechanisms partially underlying speciation.