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BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses.
Dey, Anup; Yang, Wenjing; Gegonne, Anne; Nishiyama, Akira; Pan, Richard; Yagi, Ryoji; Grinberg, Alex; Finkelman, Fred D; Pfeifer, Karl; Zhu, Jinfang; Singer, Dinah; Zhu, Jun; Ozato, Keiko.
Afiliación
  • Dey A; Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • Yang W; The DNA Sequencing and Computational Biology, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
  • Gegonne A; Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, USA.
  • Nishiyama A; Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • Pan R; Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • Yagi R; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Grinberg A; Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • Finkelman FD; Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH, USA.
  • Pfeifer K; Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • Zhu J; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Singer D; Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, USA.
  • Zhu J; The DNA Sequencing and Computational Biology, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
  • Ozato K; Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA ozatok@nih.gov.
EMBO J ; 38(7)2019 04 01.
Article en En | MEDLINE | ID: mdl-30842097
ABSTRACT
BRD4 is a BET family protein that binds acetylated histones and regulates transcription. BET/BRD4 inhibitors block blood cancer growth and inflammation and serve as a new therapeutic strategy. However, the biological role of BRD4 in normal hematopoiesis and inflammation is not fully understood. Analysis of Brd4 conditional knockout (KO) mice showed that BRD4 is required for hematopoietic stem cell expansion and progenitor development. Nevertheless, BRD4 played limited roles in macrophage development and inflammatory response to LPS ChIP-seq analysis showed that despite its limited importance, BRD4 broadly occupied the macrophage genome and participated in super-enhancer (SE) formation. Although BRD4 is critical for SE formation in cancer, BRD4 was not required for macrophage SEs, as KO macrophages created alternate, BRD4-less SEs that compensated BRD4 loss. This and additional mechanisms led to the retention of inflammatory responses in macrophages. Our results illustrate a context-dependent role of BRD4 and plasticity of epigenetic regulation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Células Madre Hematopoyéticas / Proteínas Nucleares / Biomarcadores / Regulación de la Expresión Génica / Macrófagos Peritoneales / Inflamación Límite: Animals Idioma: En Revista: EMBO J Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Células Madre Hematopoyéticas / Proteínas Nucleares / Biomarcadores / Regulación de la Expresión Génica / Macrófagos Peritoneales / Inflamación Límite: Animals Idioma: En Revista: EMBO J Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos