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Conservation of mouse-human trans-regulatory circuitry despite high cis-regulatory divergence

ABSTRACT: The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ~8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ~95% similar with that derived from human TF footprints. However, only ~20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE51341 | GEO | 2014/11/19

SECONDARY ACCESSION(S): PRJNA267242

REPOSITORIES: GEO

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Project description:Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects on gene expression are due to nearby genetic variants, trans effects are due to distal genetic variants that affect diffusible elements such as transcription factors. However, as previous studies have mostly assessed the impacts of cis and trans effects at the gene level, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we used massively parallel reporter assays to directly measure cis and trans effects between human and mouse embryonic stem cells at thousands of individual regulatory elements, including enhancers as well as promoters of both protein-coding and long non-coding RNA genes. Our approach revealed that cis effects are widespread across regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we found that trans effects are rare but stronger in enhancers than promoters, and can be attributed to a subset of transcription factors that are differentially expressed between human and mouse. While previous gene-based studies have found extensive co-occurrence of cis and trans effects in opposite directions that stabilize gene expression between species—or compensatory cis-trans effects—we find that cis-trans compensation is uncommon within individual regulatory elements. Moreover, regulatory elements that do show compensatory cis-trans effects are often less redundant than regulatory elements lacking compensatory cis-trans effects. Thus, our results are consistent with a model wherein compensatory cis-trans effects occur more often through crosstalk between multiple redundant regulatory elements than within a single individual regulatory element. Together, these results indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.

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Conservation of mouse-human trans-regulatory circuitry despite high cis-regulatory divergence

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