Previously we analysed the epigenomic differences between various T helper cells. To understand better how T cells are generated in the blood system, we decided to examine the epigenomic differences between T cell and other blood lineages. Blood develops from self-renewing hematopoietic stem cells to terminal lineages and necessitates regulator and effector gene expression changes;each cell type specifically expresses a subset of genes to carry out a specific function. Gene expression changes coincide with histone modification, histone variant deposition, and recruitment of transcription-related enzymes to specific genetic loci. Transcriptional regulation has been mostly studied using in vitro differentiation systems while epigenetic changes occurring during in vivo development remain poorly understood. By integrating previously published and novel global expression profiles from CD34+/CD133+ hematopoietic stem cells (HSCs), in vivo differentiated CD4+ T-cells and CD19+ B-cells, and in vitro differentiated CD36+ erythrocyte precursors, we identified hundreds of transcripts specifically expressed in each cell type. To relate concurrent epigenomic changes to expression, we examined genome-wide distributions of H3K4me1, H3K4me3, H3K27me1, H3K27me3, histone variant H2A.Z, ATP-dependent chromatin remodeler BRG1, and RNA Polymerase II in these cell types, as well as embryonic stem cells. These datasets revealed that numerous differentiation genes are primed for subsequent downstream expression by BRG1 and Pol II binding in HSCs, as well as bivalent modifications in the HSCs prior to their expression in downstream, differentiated cell type;much HSC bivalency is retained from embryonic stem cells. After differentiation, bivalency resolves to active chromatin configuration in the specific lineage, while bivalency remains in parallel differentiated lineages. Pol II and BRG1 are lost in closer lineages;bivalency resolves to silent monovalency in more distant lineages. Correlation of expression with epigenomic changes predicts tens of thousands of potential common and tissue-specific enhancers, which may contribute to expression patterns and differentiation pathways. Our analysis reveals how the bivalent modifications at crucial lineage factors are prepared and resolved during in vitro and in vivo differentiation. We provide a valuable dataset for further understanding the regulatory mechanisms of differentiation and function of blood lineages.

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National Heart, Lung, and Blood Institute
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Zhong, Chao; Cui, Kairong; Wilhelm, Christoph et al. (2016) Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment. Nat Immunol 17:169-78
Zhong, Chao; Cui, Kairong; Wilhelm, Christoph et al. (2016) Erratum: Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment. Nat Immunol 17:214
Ren, Gang; Cui, Kairong; Zhang, Zhiying et al. (2015) Division of labor between IRF1 and IRF2 in regulating different stages of transcriptional activation in cellular antiviral activities. Cell Biosci 5:17
Crompton, Joseph G; Narayanan, Manikandan; Cuddapah, Suresh et al. (2015) Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape. Cell Mol Immunol :
Nakatsukasa, Hiroko; Zhang, Dunfang; Maruyama, Takashi et al. (2015) The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells. Nat Immunol :
Li, Qingtian; Wang, Helen Y; Chepelev, Iouri et al. (2014) Stage-dependent and locus-specific role of histone demethylase Jumonji D3 (JMJD3) in the embryonic stages of lung development. PLoS Genet 10:e1004524
Escobar, Thelma M; Kanellopoulou, Chrysi; Kugler, David G et al. (2014) miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity 40:865-79
Yagi, Ryoji; Zhong, Chao; Northrup, Daniel L et al. (2014) The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 40:378-88
Wang, Yan; Godec, Jernej; Ben-Aissa, Khadija et al. (2014) The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-γ-producing T helper 17 cells. Immunity 40:355-66
Hu, Gangqing; Zhao, Keji (2014) Correlating histone modification patterns with gene expression data during hematopoiesis. Methods Mol Biol 1150:175-87

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