Comparative epigenomics of human and mouse erythropoiesis

Erythropoiesis is one of the best understood examples of cellular differentiation. Morphologically, erythroid differentiation proceeds in a nearly identical fashion between humans and mice, but recent evidence has shown that networks of gene expression governing this process are divergent between species. We undertook a systematic comparative analysis of six histone modifications and four transcriptional master regulators in primary pro-erythroblasts and erythroid cell lines to better understand the underlying basis of these transcriptional differences. Our analyses suggest that while chromatin structure across orthologous promoters is strongly conserved, subtle differences are associated with transcriptional divergence between species. Many transcription factor (TF) occupancy sites were poorly conserved across species (~25% for GATA1, TAL1, and NFE2), but these factors were considerably more conserved between proerythroblasts and cell lines derived from the same species. We found that certain cis-regulatory modules co-occupied by GATA1, TAL1, and KLF1 are under strict evolutionary constraint and localize to genes necessary for erythroid cell identity. More generally, we show that conserved TF occupancy sites are indicative of active regulatory regions and strong gene expression sustained during maturation. Our results suggest that evolutionary turnover of TF binding sites drives transcriptional divergence partially by mediating changes in the underlying chromatin structure. We provide examples of how this framework can be applied to understand epigenomic variation in specific regulatory regions, such as the Beta-globin gene locus. Our findings have important implications for understanding epigenomic changes that mediate variation in cellular differentiation across species, while also providing a valuable resource for studies of hematopoiesis. Examination of 6 histone marks and 4 transcription factors across human pro-erythroblasts, mouse pro-erythroblasts, K562 cells, and G1E cells 'Extract protocol' and 'library construction protocol' were performed as detailed in: GSE53983, GSE40522, GSE52924, GSE47492, GSE50406, GSE36028, GSE48020, GSE43626, GSE36985, GSE36589, GSE31477, GSE30142, GSE18868, GSE27893, GSE26501