Enhancer Turnover Is Associated with a Divergent Transcriptional Response to Glucocorticoid in Mouse and Human Macrophages

Abstract

Phenotypic differences between individuals and species are controlled in part through differences in expression of a relatively conserved set of genes. Genes expressed in the immune system are subject to especially powerful selection. We have investigated the evolution of both gene expression and candidate enhancers in human and mouse macrophages exposed to glucocorticoid (GC), a regulator of innate immunity and an important therapeutic agent. Our analyses revealed a very limited overlap in the repertoire of genes responsive to GC in human and mouse macrophages. Peaks of inducible binding of the glucocorticoid receptor (GR) detected by ChIP-Seq correlated with induction, but not repression, of target genes in both species, occured at distal regulatory sites not promoters, and were strongly enriched for the consensus GR binding motif. Turnover of GR binding between mouse and human was associated with gain and loss of the motif. There was no detectable signal of positive selection at species-specific GR binding sites, but clear evidence of purifying selection at the small number of conserved sites. We conclude that enhancer divergence underlies the difference in transcriptional activation after GC treatment between mouse and human macrophages. Only the shared inducible loci show evidence of selection and therefore these loci may be important for the subset of responses to GC that is shared between species.

Phylogenetic modeling of regulatory element turnover based on epigenomic data

“…During the past 15 years, new technologies for collecting high-throughput epigenomic data-such as chromatin immunoprecipitation and sequencing (ChIP-seq) data for transcription factors or histone modifications-have provided a path forward, by more directly indicating similarities and differences across species in molecular phenotypes that are closely related to cis-regulatory activity. A considerable number of comparative epigenomic studies have now been carried out in a variety of organisms, including studies based on transcription factor binding 17,18,[28][29][30][31] , particular histone modifications [32][33][34][35][36] , chromatin accessibility or chromatin contacts 37-39 , DNA methylation 40 , and nascent transcription 24 (partially reviewed in ref. 41 ).…”

Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression

“…Repression of many TNF-regulated enhancers and genes occurred in the absence of TNF treatment, indicating, as suggested by others (Jubb et al 2016;Oh et al 2017), that tethering between GR and p65 is not required for a primary response. Moreover, the previously described nGRE sequence was not significantly enriched within GR occupied regions, indicating that widespread repression does not occur through direct interactions between GR and nGREs in our system.…”

Protection of macrophages from intracellular pathogens by miR‐182‐5p mimic—a gene expression meta‐analysis approach

“…Interestingly, divergence was most evident in genes encoding cell surface and secreted proteins, while intracellular signaling responses were intact. In contrast, however, a comparison of mouse BMM and human MDM found very poor conservation in response to glucocorticoids [51]. The reasons for these conflicting data are not clear.…”