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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Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$584,959
Indirect Cost
Name
National Heart, Lung, and Blood Institute
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