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.2016 Jan 15;196(2):813-822.
doi: 10.4049/jimmunol.1502009. Epub 2015 Dec 9.

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

Affiliations

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

Alasdair W Jubb et al. J Immunol..

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 GC receptor (GR) detected by chromatin immunoprecipitation-Seq correlated with induction, but not repression, of target genes in both species, occurred at distal regulatory sites not promoters, and were strongly enriched for the consensus GR-binding motif. Turnover of GR binding between mice and humans 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.

Copyright © 2016 by The American Association of Immunologists, Inc.

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Figures

Figure 1
Figure 1. The expression response of macrophages to dexamethasone is divergent despite target gene promoter sequence conservation
(A) For each time point studied heatmaps of genes regulated by 100nM dexamethasone in hMDM alongside the orthologous genes from mouse and their expression values in mBMDM with height proportional to the number of genes changing (red = induced, blue = repressed). (B) The inverse analysis to that in (A) showing genes regulated in mBMDM by 100nM dexamethasone alongside their human orthologues. (C) Box plots showing average sequence conservation scores (phastCons) of promoters for; (all Hs) all human genes, genes responding only in either hMDM (Hs specific) or mBMDM (Mm specific) and genes with a shared expression response (shared). (D & E) as in (C) but for all genes regulated by GC in (D) mBMDM and (E) hMDM, categorised by response and kinetics. All Refseq promoters are shown as a measure of background. (*** p <1×10−10, ** p <1×10−4, * p <0.05, Wilcoxon rank sum; n = number of promoters; median = horizontal bar, whiskers = 1.5x interquartile range, statistical comparisons are made to background).
Figure 2
Figure 2. GR binding in mBMDM and hMDM occurs at sites with the canonical GRE
(A) ChIP-seq data tracks from the UCSC browser for the Fos – Jdp2 region, for GR binding in mBMDM. Data from ChIP with anti-GR antibodies after treatment with 100nM dexamethasone for 2h (Dex GR IP), input material (Dex input) and immunoprecipitated material from a vehicle treated control (Vehicle GR IP) are shown. (C) As in (A) but for FOS – JDP2 in hMDM. Vehicle GR IP data was not generated in hMDM due to constraints on available cell numbers. A GR bound site that aligns between mBMDM and hDMD is highlighted in green. Alignments are to mm9 and hg19 versions of the mouse and human genomes, respectively. (B and D) Enriched motifs found de novo within GR bound sites in mBMDM (B) and hMDM (D). (E) Evolutionary outcomes for GR peaks in human. Aligned sites where the orthologous region is bound by GR in mouse are shown in green and in yellow if the site is not bound by GR in mouse. Sites that could not be aligned are defined as either insertions (purple) or deletions (red) by comparison with dog (CanFam2), horse (EquCab2), cow (BosTau6) and pig (SuScr3) genomes (see methods), Human GR sites were assigned as deletions in the mouse lineage.
Figure 3
Figure 3. Induced genes are associated with GR binding
(A and B) The proportion of GR ChIP peaks with induced (green line) or repressed (red line) gene promoters within a given genomic distance for (A) mBMDM and (B) hMDM. The 95% confidence intervals from matched genome permuted distributions of GR peaks are shown in grey. (C and D) Enrichment of the proportion of induced (green line) gene promoters with a GR peak within a given interval versus the proportion of induced genes without a GR peak (red line) within that interval for (C) mBMDM and (D) hMDM. No enrichment is seen for repressed genes (shown in red) The 95% confidence interval from a genome permuted distribution of GR peaks is shown in grey.
Figure 4
Figure 4. GR binding sites are minimally conserved between mouse and man and this is linked to the divergent transcriptional response to GC
(A) GR ChIP-seq data from mBMDM (orange) and hMDM (cyan) showing conserved GR binding (green highlight) at a locus (DUSP1/Dusp1) whose expression is rapidly induced by GC in both mouse and human macrophages. GR bound sites aligned between species are linked by light green highlight: the most prominent sites are bound in only one species. (B) Enrichment / depletion for mouse/human shared GR binding within 1Mb for GC-responsive genes that are; shared between mouse and human (green), mouse-specific (cyan), human-specific (orange). Numbers give raw counts for each category. (C) As in (A) but showing mouse-specific GR binding at F13a1/F13A1 which is induced in mBMDM but not hMDM. (D) As for B, but for mouse-specific GR binding sites. The chi squared p value for the difference between mouse and human specific sites is given. (E) As in (A) but showing human-specific GR binding at ADORA3/Adora3 which is induced in hMDM but not mBMDM. (F) As for (D) but for human-specific GR-binding sites. Expanded windows for F13A1 and Adora3 are shown in Figures S1D.
Figure 5
Figure 5. Conserved GR binding is linked to conservation of the GRE
(A) Motif enrichment for the sites bound by GR in mBMDM that aligned and were also bound in hMDM, using as background the mouse sites that could be aligned to human but were not bound in hMDM (q values shown, Benjamini-Hochberg). (B) Analogous to (A) but for hMDM sites bound in mBMDM vs sites that could be aligned but were not bound in mBMDM. (C) Mean per base constraint scores calculated using GERP (72) across the GRE in shared (green) and species-specific (red) peaks found in hMDM, where the grey bars represents the standard error of the mean. Vertical dashed lines delineate the centre NNN for the GRE, as derived de novo from our hMDM data. (D) Analogous to (C) for GR bound peaks and GRE motif found in mBMDM.
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