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Cell Rep. 2017 Aug 15;20(7):1597-1608. doi: 10.1016/j.celrep.2017.07.067.

Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis.

Author information

1
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA. Electronic address: n.palpant@imb.uq.edu.au.
2
Department of Computer Science, University of Washington School of Medicine, Seattle, WA 98109, USA.
3
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
4
Department of Bioengineering, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
5
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
6
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA.
8
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington School of Medicine, Seattle, WA 98109, USA; Department of Medicine/Cardiology, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA. Electronic address: murry@uw.edu.

Abstract

We analyzed chromatin dynamics and transcriptional activity of human embryonic stem cell (hESC)-derived cardiac progenitor cells (CPCs) and KDR+/CD34+ endothelial cells generated from different mesodermal origins. Using an unbiased algorithm to hierarchically rank genes modulated at the level of chromatin and transcription, we identified candidate regulators of mesodermal lineage determination. HOPX, a non-DNA-binding homeodomain protein, was identified as a candidate regulator of blood-forming endothelial cells. Using HOPX reporter and knockout hESCs, we show that HOPX regulates blood formation. Loss of HOPX does not impact endothelial fate specification but markedly reduces primitive hematopoiesis, acting at least in part through failure to suppress Wnt/β-catenin signaling. Thus, chromatin state analysis permits identification of regulators of mesodermal specification, including a conserved role for HOPX in governing primitive hematopoiesis.

KEYWORDS:

Wnt signaling; cardiac; cardiovascular; chromatin dynamics; differentiation; epigenetics; genome engineering; hematopoiesis; human pluripotent stem cell

PMID:
28813672
PMCID:
PMC5576510
DOI:
10.1016/j.celrep.2017.07.067
[Indexed for MEDLINE]
Free PMC Article

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