title: RNA polymerase II pausing modulates hematopoietic stem cell emergence in zebrafish.
abstract: The promoter-proximal pausing of RNA polymerase II (Pol II) plays a critical role in regulating metazoan gene transcription. Despite the prevalence of Pol II pausing across the metazoan genomes, little is known about the in vivo effect of Pol II pausing on vertebrate development. We use the emergence of hematopoietic stem cells (HSCs) in zebrafish embryos as a model to investigate the role of Pol II pausing in vertebrate organogenesis. Disrupting Pol II pausing machinery causes a severe reduction of HSC specification, a defect that can be effectively rescued by inhibiting Pol II elongation. In pausing-deficient embryos, the transforming growth factor β (TGFβ) signaling is elevated due to enhanced transcription elongation of key pathway genes, leading to HSC inhibition; in contrast, the interferon-γ (IFN-γ) signaling and its downstream effector Jak2/Stat3, which are required for HSC formation, are markedly attenuated owing to reduced chromatin accessibility on IFN-γ receptor genes. These findings reveal a novel transcription mechanism instructing HSC fate by pausing-mediated differential regulation of key signaling pathways.
authors: Laboratory of Molecular Genetics of Blood Development, Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Qiwen
authors: Q
authors: Yang
authors: Laboratory of Molecular Genetics of Blood Development, Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Xiuli
authors: X
authors: Liu
authors: Laboratory of Molecular Genetics of Blood Development, Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Ting
authors: T
authors: Zhou
authors: Laboratory of Molecular Genetics of Blood Development, Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Jennifer
authors: J
authors: Cook
authors: Laboratory of Molecular Genetics of Blood Development, Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Kim
authors: K
authors: Nguyen
authors: Laboratory of Molecular Genetics of Blood Development, Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX.
authors: Xiaoying
authors: X
authors: Bai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D049109:Cell Proliferation / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013559:Symbiosis; D061805:Transcription Elongation, Genetic; D035602:Transcriptional Elongation Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D017471:Receptors, Interferon; D050796:STAT3 Transcription Factor; D035602:Transcriptional Elongation Factors; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; D000096743:Interferon gamma Receptor; C112224:SUPT5H protein, human; C494089:stat3 protein, zebrafish; C069940:SPT5 transcriptional elongation factor