SummaryAs the premier model organism in biomedical research, the laboratory mouse shares the majority of protein-coding genes with humans, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications, and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of other sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.
Hox genes encode homeodomain-containing transcription factors that pattern the body axes of animal embryos. It is well established that the exquisite DNA-binding specificity that allows different Hox proteins to specify distinct structures along the body axis is frequently dependent on interactions with other DNA-binding proteins which act as Hox cofactors. These include the PBC and MEIS classes of TALE (Three Amino acid Loop Extension) homeodomain proteins. The PBC class comprises fly Extradenticle (Exd) and vertebrate Pbx homeoproteins, whereas the MEIS class includes fly Homothorax (Hth) and vertebrate Meis and Prep homeoproteins. Exd was first implicated as a Hox cofactor based on mutant phenotypes in the fly. In vertebrates, PBC and MEIS homeobox proteins play important roles in development and disease. In this review, we describe the evidence that these functions reflect a requirement for Pbx and Meis/Prep proteins as Hox cofactors. However, there is mounting evidence that, like in the fly, Pbx and Meis/Prep proteins function more broadly, and we also discuss how "Hox cofactors" function as partners for other, non-Hox transcription factors during development. Conversely, we review the evidence that Hox proteins have functions that are independent of Pbx and Meis/Prep cofactors and discuss the possibility that other proteins may participate in the DNA-bound Hox complex, contributing to DNA-binding specificity in the absence of, or in addition to, Pbx and Meis/Prep.
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.
To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes.
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