Genome-wide transcription factor–binding maps reveal cell-specific changes in the regulatory architecture of human HSPCs

Subramanian, Shruthi and Thoms, Julie A. I. and Huang, Yizhou and Cornejo-Páramo, Paola and Koch, Forrest C. and Jacquelin, Sebastien and Shen, Sylvie and Song, Emma and Joshi, Swapna and Brownlee, Chris and Woll, Petter S. and Chacon-Fajardo, Diego and Beck, Dominik and Curtis, David J. and Yehson, Kenneth and Antonenas, Vicki and O'Brien, Tracey and Trickett, Annette and Powell, Jason A. and Lewis, Ian D. and Pitson, Stuart M. and Gandhi, Maher K. and Lane, Steven W. and Vafaee, Fatemeh and Wong, Emily S. and Göttgens, Berthold and Alinejad-Rokny, Hamid and Wong, Jason W. H. and Pimanda, John E. (2023) Genome-wide transcription factor–binding maps reveal cell-specific changes in the regulatory architecture of human HSPCs. Blood, 142 (17). pp.1448-1462. ISSN 0006-4971

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Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay among transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs (FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2) bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remains unknown. We mapped genome-wide chromatin contacts (HiC, H3K27ac, HiChIP), chromatin modifications (H3K4me3, H3K27ac, H3K27me3) and 10 TF binding profiles (heptad, PU.1, CTCF, STAG2) in HSPC subsets (stem/multipotent progenitors plus common myeloid, granulocyte macrophage, and megakaryocyte erythrocyte progenitors) and found TF occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. Furthermore, heptad-occupied regions in HSPCs were subsequently bound by lineage-defining TFs, including PU.1 and GATA1, suggesting that heptad factors may prime regulatory elements for use in mature cell types. We also found that enhancers with cell-type-specific heptad occupancy shared a common grammar with respect to TF binding motifs, suggesting that combinatorial binding of TF complexes was at least partially regulated by features encoded in DNA sequence motifs. Taken together, this study comprehensively characterizes the gene regulatory landscape in rare subpopulations of human HSPCs. The accompanying data sets should serve as a valuable resource for understanding adult hematopoiesis and a framework for analyzing aberrant regulatory networks in leukemic cells.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 01 May 2024 05:05
Last Modified: 01 May 2024 05:05

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