Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells
- Peng Gao1,10,
- Changya Chen1,10,
- Elizabeth D. Howell2,3,10,
- Yan Li2,8,10,
- Joanna Tober2,
- Yasin Uzun1,
- Bing He1,9,
- Long Gao4,
- Qin Zhu5,
- Arndt F. Siekmann2,
- Nancy A. Speck2,6 and
- Kai Tan1,2,4,7
- 1Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
- 2Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 3Graduate Group in Cell and Molecular Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 4Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 5Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 6Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 7Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Corresponding authors: tank1{at}email.chop.edu; nancyas{at}upenn.edu
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↵10 These authors contributed equally to this work.
Abstract
Hematopoietic stem cell (HSC) ontogeny is accompanied by dynamic changes in gene regulatory networks. We performed RNA-seq and histone mark ChIP-seq to define the transcriptomes and epigenomes of cells representing key developmental stages of HSC ontogeny in mice. The five populations analyzed were embryonic day 10.5 (E10.5) endothelium and hemogenic endothelium from the major arteries, an enriched population of prehematopoietic stem cells (pre-HSCs), fetal liver HSCs, and adult bone marrow HSCs. Using epigenetic signatures, we identified enhancers for each developmental stage. Only 12% of enhancers are primed, and 78% are active, suggesting the vast majority of enhancers are established de novo without prior priming in earlier stages. We constructed developmental stage-specific transcriptional regulatory networks by linking enhancers and predicted bound transcription factors to their target promoters using a novel computational algorithm, target inference via physical connection (TIPC). TIPC predicted known transcriptional regulators for the endothelial-to-hematopoietic transition, validating our overall approach, and identified putative novel transcription factors, including the broadly expressed transcription factors SP3 and MAZ. Finally, we validated a role for SP3 and MAZ in the formation of hemogenic endothelium. Our data and computational analyses provide a useful resource for uncovering regulators of HSC formation.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.338202.120.
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Freely available online through the Genes & Development Open Access option.
- Received March 6, 2020.
- Accepted April 28, 2020.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.