title: Structure of Nascent Chromatin Is Essential for Hematopoietic Lineage Specification.
abstract: The role of chromatin structure in lineage commitment of multipotent hematopoietic progenitors (HPCs) is presently unclear. We show here that CD34+HPCs possess a post-replicative chromatin globally devoid of the repressive histone mark H3K27me3. This H3K27-unmodified chromatin is required for recruitment of lineage-determining transcription factors (TFs) C/EBPα, PU.1, and GATA-1 to DNA just after DNA replication upon cytokine-induced myeloid or erythroid commitment. Blocking DNA replication or increasing H3K27me3 levels prevents recruitment of these TFs to DNA and suppresses cytokine-induced erythroid or myeloid differentiation. However, H3K27me3 is rapidly associated with nascent DNA in more primitive human and murine HPCs. Treatment of these cells with instructive cytokines leads to a significant delay in accumulation of H3K27me3 in nascent chromatin due to activity of the H3K27me3 demethylase UTX. Thus, HPCs utilize special mechanisms of chromatin modification for recruitment of specific TFs to DNA during early stages of lineage specification.
authors.affiliation: Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Petruk
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Samanta A
authors.initials: SA
authors.lastname: Mariani
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: De Dominici
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Porazzi
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Minieri
authors.affiliation: Department of Neuroscience, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jingli
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Neuroscience, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Iacovitti
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Flomenberg
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: bruno.calabretta@jefferson.edu.
authors.forename: Bruno
authors.initials: B
authors.lastname: Calabretta
authors.affiliation: Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: alexander.mazo@jefferson.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mazo
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D018952:Antigens, CD34; D022763:CCAAT-Enhancer-Binding Protein-alpha; D002843:Chromatin; D050982:GATA1 Transcription Factor; D056484:Jumonji Domain-Containing Histone Demethylases; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494689:Gata1 protein, mouse; C523761:Kdm6b protein, mouse
keywords: DNA replication; H3K27me3; HMTs; KDMs; hematopoietic progenitors; myeloid and erythroid differentiation; nascent DNA; nascent chromatin; transcription factors