TY - JOUR
T1 - RNA polymerase II pausing modulates hematopoietic stem cell emergence in zebrafish
AU - Yang, Qiwen
AU - Liu, Xiuli
AU - Zhou, Ting
AU - Cook, Jennifer
AU - Nguyen, Kim
AU - Bai, Xiaoying
N1 - Funding Information:
This work was supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants R00DK088963 and R01DK105287 (X.B.), the Cancer Prevention Research Institute of Texas (CPRIT R1115) (X.B.), and the Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research at UTSW.
Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016/9/29
Y1 - 2016/9/29
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2016-02-697847
DO - 10.1182/blood-2016-02-697847
M3 - Article
C2 - 27520065
AN - SCOPUS:85026691364
SN - 0006-4971
VL - 128
SP - 1701
EP - 1710
JO - Blood
JF - Blood
IS - 13
ER -