title: Scl binds to primed enhancers in mesoderm to regulate hematopoietic and cardiac fate divergence.
abstract: Scl/Tal1 confers hemogenic competence and prevents ectopic cardiomyogenesis in embryonic endothelium by unknown mechanisms. We discovered that Scl binds to hematopoietic and cardiac enhancers that become epigenetically primed in multipotent cardiovascular mesoderm, to regulate the divergence of hematopoietic and cardiac lineages. Scl does not act as a pioneer factor but rather exploits a pre-established epigenetic landscape. As the blood lineage emerges, Scl binding and active epigenetic modifications are sustained in hematopoietic enhancers, whereas cardiac enhancers are decommissioned by removal of active epigenetic marks. Our data suggest that, rather than recruiting corepressors to enhancers, Scl prevents ectopic cardiogenesis by occupying enhancers that cardiac factors, such as Gata4 and Hand1, use for gene activation. Although hematopoietic Gata factors bind with Scl to both activated and repressed genes, they are dispensable for cardiac repression, but necessary for activating genes that enable hematopoietic stem/progenitor cell development. These results suggest that a unique subset of enhancers in lineage-specific genes that are accessible for regulators of opposing fates during the time of the fate decision provide a platform where the divergence of mutually exclusive fates is orchestrated.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
authors.forename: Tõnis
authors.initials: T
authors.lastname: Org
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Duan
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, CA, USA Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
authors.forename: Amelie
authors.initials: A
authors.lastname: Montel-Hagen
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Van Handel
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute Harvard Stem Cell Institute Harvard Medical School, Boston, MA, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Kerényi
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Sasidharan
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
authors.forename: Liudmilla
authors.initials: L
authors.lastname: Rubbi
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute Harvard Stem Cell Institute Harvard Medical School, Boston, MA, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute Harvard Stem Cell Institute Harvard Medical School, Boston, MA, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, CA, USA Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, USA.
authors.forename: Siavash K
authors.initials: SK
authors.lastname: Kurdistani
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, USA hmikkola@mcdb.ucla.edu.
authors.forename: Hanna Ka
authors.initials: HK
authors.lastname: Mikkola
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D015723:Gene Library; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006801:Humans; D008648:Mesoderm / Q000196:embryology* / Q000378:metabolism; D046228:Microarray Analysis; D008954:Models, Biological; D008969:Molecular Sequence Data; D032386:Myoblasts, Cardiac / Q000166:cytology* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C067143:TAL1 protein, human
keywords: cardiac specification; enhancer; hematopoiesis; mesoderm diversification; transcriptional regulation