Enhancer Divergence and cis-Regulatory Evolution in the Human and Chimp Neural Crest

Abstract

Summary Cis-regulatory changes play a central role in morphological divergence, yet the regulatory principles underlying emergence of human traits remain poorly understood. Here we use epigenomic profiling from human and chimpanzee cranial neural crest cells to systematically and quantitatively annotate divergence of craniofacial cis-regulatory landscapes. Epigenomic divergence is attributable to genetic variation within TF motifs at orthologous enhancers, with a novel motif being most predictive of activity biases. We explore properties of this cis-regulatory change, revealing the role of particular retroelements, uncovering broad clusters of species-biased enhancers near genes associated with human facial variation, and demonstrating that cis-regulatory divergence is linked to quantitative expression differences of crucial neural crest regulators. Our work provides a wealth of candidates for future evolutionary studies and demonstrates the value of ‘cellular anthropology’, a strategy of using in vitro-derived embryonic cell types to elucidate both fundamental and evolving mechanisms underlying morphological variation in higher primates.

Comparative analyses of super-enhancers reveal conserved elements in vertebrate genomes

“…It remains to be determined if those SEs with orthologous gene associations have an evolutionary common origin, or if they independently evolved in the three species. Notably, enhancers shared between human and chimp also display higher sequence conservation than species-biased enhancers (Prescott et al 2015).…”

“…Enhancers are cisregulatory elements able to recruit transcription factors (TFs) and the transcriptional apparatus to activate their target gene expression (Smith and Shilatifard 2014;Heinz et al 2015;Ren and Yue 2015). Chromatin immunoprecipitation followed by highthroughput sequencing (ChIP-seq) has been a frequently used strategy to generate genome-wide enhancer annotations (Visel et al 2009;Bernstein et al 2010;Creyghton et al 2010;RadaIglesias et al 2011;Kieffer-Kwon et al 2013;Vermunt et al 2014;Prescott et al 2015;Villar et al 2015). ChIP-seq-based approaches have shown that a subset of mammalian enhancers are found in close sequence proximity to one another, forming large regions of hyperactive chromatin referred to as super-enhancers (SEs) or stretch enhancers (Lovén et al 2013;Parker et al 2013;Whyte et al 2013).…”

Yap and Taz play a crucial role in neural crest-derived craniofacial development

“…8J). Craniofacial cis-regulatory landscapes were recently studied by deep-sequencing of transposase-accessible chromatin (ATAC-seq) in human and chimpanzee cranial neural crest cells (Prescott et al, 2015). Bioinformatic analysis of these data sets (Gene Expression Omnibus, accession no.…”

Deep homology in the age of next-generation sequencing

“…Expanding such rationale to a comparative level, between cell lines and organoids from different organisms, will allow for a reductionist approach to character identity development. Moreover, cell culture-based assays for large-scale comparative studies of epigenomic states and enhancer activities can function as invaluable proxies to delineate regulatory logic across species boundaries [93,94].…”