title: Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis.
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.
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Pediatric Residency Program, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA;
authors.forename: Maxim
authors.initials: M
authors.lastname: Pimkin
authors.affiliation: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia 19019, Pennsylvania, USA;
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania 16802, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Tejaswini
authors.initials: T
authors.lastname: Mishra
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania 16802, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Christapher S
authors.initials: CS
authors.lastname: Morrissey
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania 16802, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Weisheng
authors.initials: W
authors.lastname: Wu
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania 16802, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Keller
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Blobel
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beer
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania 16802, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Ross C
authors.initials: RC
authors.lastname: Hardison
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; weissmi@email.chop.edu rch8@psu.edu.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001665:Binding Sites; D002454:Cell Differentiation; D019070:Cell Lineage; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D004920:Erythropoiesis / Q000502:physiology*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D059372:Nucleotide Motifs; D011485:Protein Binding; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D034061:Thrombopoiesis / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D006657:Histones; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C489366:Tal1 protein, mouse