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Cited by 57Genomics and Chromatin DynamicsHematopoietic Stem Cell TransplantationChromatin Remodeling and Cancer

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

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Subramanian, Shruthi, Thoms, Julie A. I., Huang, Yizhou, Cornejo-Páramo, Paola, Koch, Forrest C., Jacquelin, Sebastien, Shen, Sylvie, Song, Emma +21 more·2023·Blood
DOI 10.1182/blood.2023021120PMC PMC10651876
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Abstract

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.

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  • Genome-wide datasets of TF binding and chromatin accessibility are not informative regarding the functional role of each TF in a given sequence context.

    “Genome-wide datasets of TF binding and chromatin accessibility13,22,23 are not informative regarding the functional role of each TF in a given sequence context.”

    From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [22]

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Authors
Subramanian, S., Thoms, J. A. I., Huang, Y., Cornejo-Páramo, P., Koch, F. C., Jacquelin, S., Shen, S., Song, E., Joshi, S., Brownlee, C., Woll, P. S., Chacon-Fajardo, D., Beck, D., Curtis, D. J., Yehson, K., Antonenas, V., O'Brien, T., Trickett, A., Powell, J. A., Lewis, I. D., Pitson, S. M., Gandhi, M. K., Lane, S. W., Vafaee, F., Wong, E. S., Göttgens, B., Alinejad-Rokny, H., Wong, J. W. H., & Pimanda, J. E.
Affiliations
  • UNSW Sydney (AU)
  • University of Technology Sydney (AU)
  • 4Victor Chang Cardiac Research Institute, Sydney, Australia
  • 6Macrophage Biology Laboratory, Mater Research, Brisbane, Australia
  • Prince of Wales Hospital (AU)
  • Karolinska Institutet (SE)
  • 3Centre for Health Technologies and the School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
  • Monash University (AU)
  • NSW Health Pathology (AU)
  • Sydney Children's Hospital (AU)
  • South Australia Pathology (AU)
  • The University of Queensland (AU)
  • QIMR Berghofer Medical Research Institute (AU)
  • Victor Chang Cardiac Research Institute (AU)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • University of Hong Kong (HK)
Corresponding author
  • Thoms, Julie A. I.
  • Wong, Jason W. H.
  • Pimanda, John E.
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2023-10-26
Volume
142
Issue
17
Pages
1448-1462
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2023021120
PMC
PMC10651876
OpenAlex
W4385972047
Cited by
57
References
11
Citations by year
2026: 19 · 2025: 21 · 2024: 13 · 2023: 4
FWCI
5.01
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Blood (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Anthony Rothe Memorial Trust
  • Wellcome Trust (206328/Z/17/Z, 206328)
  • Medical Research Council (MC_PC_17230)
  • National Health and Medical Research Council (2011627, 1139787)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
hematopoietic stem and progenitor cells, transcription factor binding, FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2, hematopoietic differentiation, enhancer-promoter interactions, chromatin accessibility, H3K27ac, H3K4me3, H3K27me3, PU.1, CTCF, STAG2, GATA-1, DNA sequence motifs, hematopoiesis, leukemia
MeSH terms
Chromatin, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Humans, Core Binding Factor Alpha 2 Subunit

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