Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis
- Maxim Pimkin1,2,8,9,
- Andrew V. Kossenkov3,8,
- Tejaswini Mishra4,5,
- Christapher S. Morrissey4,5,
- Weisheng Wu4,5,10,
- Cheryl A. Keller4,5,
- Gerd A. Blobel1,6,
- Dongwon Lee7,
- Michael A. Beer7,
- Ross C. Hardison4,5 and
- Mitchell J. Weiss1,11
- 1Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
- 2Pediatric Residency Program, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA;
- 3Center for Systems and Computational Biology, The Wistar Institute, Philadelphia 19019, Pennsylvania, USA;
- 4Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
- 5Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
- 6University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 7McKusick-Nathans Institute of Genetic Medicine and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Corresponding authors: weissmi{at}email.chop.edu, rch8{at}psu.edu
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↵8 These authors contributed equally to this work.
Abstract
Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.164178.113.
Freely available online through the Genome Research Open Access option.
- Received July 26, 2013.
- Accepted January 29, 2014.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0.
