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Blood Adv. 2018 Oct 23;2(20):2691-2703. doi: 10.1182/bloodadvances.2018019448.

MRTFA augments megakaryocyte maturation by enhancing the SRF regulatory axis.

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Department of Cell Biology.
Department of Pediatrics.
Department of Laboratory Medicine.
Department of Pathology.
Department of Genetics, and.
Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT.
Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WA.
Signaling and Transcription Group, Cancer Research UK London Research Institute, London, United Kingdom.
Transcriptional Control in Inflammation and Cancer Group, Humanitas University, Milan, Italy; and.
Transcription & Epigenomics in Developing T-Cells Group, Institut de Génétique Moléculaire de Montpellier-Unité Mixte de Recherche 5535 Centre National de la Recherche Scientifique, Montpellier, France.


Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds DNA at CArG (CC[A/T]6GG) domains in association with myocardin-family proteins (eg, myocardin-related transcription factor A [MRTFA]) or the ternary complex factor family of E26 transformation-specific (ETS) proteins. In primary hematopoietic cells, knockout of either SRF or MRTFA decreases megakaryocyte (Mk) maturation causing thrombocytopenia. The human erythroleukemia (HEL) cell line mimics the effects of MRTFA on Mk maturation, and MRTFA overexpression (MRTFAOE) in HEL cells enhances megakaryopoiesis. To identify the mechanisms underlying these effects, we performed integrated analyses of anti-SRF chromatin immunoprecipitation (ChIP) and RNA-sequencing data from noninduced and phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA])-induced HEL cells, with and without MRTFAOE We found that 11% of genes were upregulated with TPA induction, which was enhanced by MRTFAOE, resulting in an upregulation of 25% of genes. MRTFAOE increased binding of SRF to genomic sites and enhanced TPA-induced expression of SRF target genes. The TPA-induced genes are predicted to be regulated by SRF and ETS factors, whereas those upregulated by TPA plus MRTFAOE lack ETS binding motifs, and MRTFAOE skews SRF binding to genomic regions with CArG sites in regions relatively lacking in ETS binding motifs. Finally, ChIP-polymerase chain reaction using HEL cells and primary human CD34+ cell-derived subpopulations confirms that both SRF and MRTFA have increased binding during megakaryopoiesis at upregulated target genes (eg, CORO1A). We show for the first time that MRTFA increases both the genomic association and activity of SRF and upregulates genes that enhance primary human megakaryopoiesis.

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