HDAC1 and HDAC2 Modulate TGF-β Signaling during Endothelial-to-Hematopoietic Transition.pdf (4.97 MB)
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HDAC1 and HDAC2 Modulate TGF-β Signaling during Endothelial-to-Hematopoietic Transition

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journal contribution
posted on 09.08.2018, 13:40 by Roshana Thambyrajah, Muhammad Z. H. Fadlullah, Martin Proffitt, Rahima Patel, Shaun M. Cowley, Valerie Kouskoff, Georges Lacaud
The first hematopoietic stem and progenitor cells are generated during development from hemogenic endothelium (HE) through trans-differentiation. The molecular mechanisms underlying this endothelial-to-hematopoietic transition (EHT) remain poorly understood. Here, we explored the role of the epigenetic regulators HDAC1 and HDAC2 in the emergence of these first blood cells in vitro and in vivo. Loss of either of these epigenetic silencers through conditional genetic deletion reduced hematopoietic transition from HE, while combined deletion was incompatible with blood generation. We investigated the molecular basis of HDAC1 and HDAC2 requirement and identified TGF-β signaling as one of the pathways controlled by HDAC1 and HDAC2. Accordingly, we experimentally demonstrated that activation of this pathway in HE cells reinforces hematopoietic development. Altogether, our results establish that HDAC1 and HDAC2 modulate TGF-β signaling and suggest that stimulation of this pathway in HE cells would be beneficial for production of hematopoietic cells for regenerative therapies.

Funding

The authors thank the Biological Resources Unit, Advanced Imaging and Flow Cytometry, the Molecular Biology Core Facility, and Histology facilities for technical support and Julia Draper, Michael Lie-a-Ling, and Rui Monteiro for critical reading of the manuscript. Research in the authors' laboratory is supported by the Medical Research Council (MR/P000673/1 to V.K. and MR/J009202/1 to S.M.C.), the Biotechnology and Biological Sciences Research Council (BB/I001794/1 to G.L. and V.K. and BB/N002954/1 to S.M.C.), Bloodwise (12037), the European Union's Horizon 2020 (GA6586250), and Cancer Research UK (C5759/A20971).

History

Citation

Stem Cell Reports, 2018, 10 (4), pp. 1369-1383

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Stem Cell Reports

Publisher

Elsevier (Cell Press)

eissn

2213-6711

Acceptance date

13/03/2018

Copyright date

2018

Available date

09/08/2018

Publisher version

https://www.sciencedirect.com/science/article/pii/S2213671118301383?via=ihub

Notes

The sequencing read files from the RNA and ChIP sequencing are available through GEO: GSE101683. Supplemental Information includes Supplemental Experimental Procedures, seven figures, two tables, and five videos and can be found with this article online at https://doi.org/10.1016/j.stemcr.2018.03.011.

Language

en