Conservation of trans-acting circuitry during mammalian regulatory evolution

Abstract

The fundamental body plan and major physiological axes have been highly conserved during mammalian evolution, despite constraint of only a fraction of the human genome sequence. To quantify cis- vs. trans-regulatory 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 TF occupancy sites at nucleotide resolution. Here we show that mouse TF footprints encode a regulatory lexicon of >600 motifs that is >95% similar with that recognized in vivo by human TFs. However, only ~20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape around each TF gene, 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. Strikingly, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results suggest that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry.

Models of human core transcriptional regulatory circuitries

“…These global studies have provided foundational resources and important insights into basic principles governing transcriptional regulatory networks. These include the identification of recurring motifs of regulatory interactions (Lee et al 2002;Alon 2007;Davidson 2010;Stergachis et al 2014) and of groups of genes that participate in common biological processes (Bar-Joseph et al 2003;Dutkowski et al 2013). …”

Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profiles

“…These sets of DNase I-hypersensitive regions are derived from 458 human and 116 mouse DNase-seq profiles. The unions of DNase I hypersensitive regions from these public DNase-seq profiles (Neph et al 2012a;Thurman et al 2012;Stergachis et al 2014) include approximately 2.7 million and 1.5 million regions in human and mouse, respectively (more details can be found in the Supplemental Methods section). The H3K27ac ChIP-seq read counts across 1-kb genomic intervals centered on each UDHS region are summarized (Fig.…”

A deeper confusion

“…Parrington notes that a large fraction of the identified putative regulatory elements show little conservation between human and mouse, as revealed by the parallel mouse ENCODE project (Yue et al 2014;Cheng et al 2014;Stergachis et al 2014). This is indeed a fascinating and very important observation, but its real significance is not that it highlights the uniqueness of humans, as interpreted in the book, but that it actually supports the view that mammalian genomes are shaped in large part by neutral evolutionary forces (Villar et al 2014;Marinov 2014).…”