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Disruption of a GAT...
Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells
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- Thoms, Julie A.I. (author)
- University of New South Wales
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- Truong, Peter (author)
- University of New South Wales
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- Subramanian, Shruthi (author)
- University of New South Wales
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- Knezevic, Kathy (author)
- University of New South Wales
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- Harvey, Gregory (author)
- University of New South Wales
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- Huang, Yizhou (author)
- University of Technology Sydney
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- Seneviratne, Janith A. (author)
- University of New South Wales
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- Carter, Daniel R. (author)
- University of Technology Sydney
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- Joshi, Swapna (author)
- University of New South Wales
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- Skhinas, Joanna (author)
- University of New South Wales
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- Chacon, Diego (author)
- University of Technology Sydney
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- Shah, Anushi (author)
- University of New South Wales
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- de Jong, Ineke (author)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine
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- Beck, Dominik (author)
- University of Technology Sydney,University of New South Wales
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- Göttgens, Berthold (author)
- University of Cambridge
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- Larsson, Jonas (author)
- Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,WCMM- Wallenberg center för molekylär medicinsk forskning,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,WCMM-Wallenberg Centre for Molecular Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Wong, Jason W.H. (author)
- University of Hong Kong
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- Zanini, Fabio (author)
- University of New South Wales,Garvan Institute of Medical Research
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- Pimanda, John E. (author)
- Prince of Wales Hospital,University of New South Wales
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(creator_code:org_t)
- American Society of Hematology, 2021
- 2021
- English 15 s.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 138:16, s. 1441-1455
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http://dx.doi.org/10...
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https://doi.org/10.1...
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Abstract
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- Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation, but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesized that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, and RUNX1) bind key hematopoietic genes in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal hematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. In this study, we integrated bulk and single-cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists, with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and leukemic cells. The heptad factors GATA2, TAL1, and ERG formed an integrated subcircuit that regulates stem cell-to-erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits can be harnessed to promote specific cell-type transitions and overcome dysregulated hematopoiesis.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
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- ref (subject category)
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Blood
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- By the author/editor
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Thoms, Julie A.I ...
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Truong, Peter
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Subramanian, Shr ...
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Knezevic, Kathy
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Harvey, Gregory
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Huang, Yizhou
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show more...
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Seneviratne, Jan ...
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Carter, Daniel R ...
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Joshi, Swapna
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Skhinas, Joanna
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Chacon, Diego
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Shah, Anushi
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de Jong, Ineke
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Beck, Dominik
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Göttgens, Bertho ...
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Larsson, Jonas
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Wong, Jason W.H.
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Zanini, Fabio
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Pimanda, John E.
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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Blood
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Lund University