PICH Supports Embryonic Hematopoiesis by Suppressing a cGAS-STING-Mediated Interferon Response
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PICH Supports Embryonic Hematopoiesis by Suppressing a cGAS-STING-Mediated Interferon Response. / Geng, Xinwei; Zhang, Chao; Li, Miao; Wang, Jiaqi; Ji, Fang; Feng, Hanrong; Xing, Meichun; Li, Fei; Zhang, Lingling; Li, Wen; Chen, Zhihua; Hickson, Ian D.; Shen, Huahao; Ying, Songmin.
In: Advanced Science, Vol. 9, No. 7, 2103837, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - PICH Supports Embryonic Hematopoiesis by Suppressing a cGAS-STING-Mediated Interferon Response
AU - Geng, Xinwei
AU - Zhang, Chao
AU - Li, Miao
AU - Wang, Jiaqi
AU - Ji, Fang
AU - Feng, Hanrong
AU - Xing, Meichun
AU - Li, Fei
AU - Zhang, Lingling
AU - Li, Wen
AU - Chen, Zhihua
AU - Hickson, Ian D.
AU - Shen, Huahao
AU - Ying, Songmin
N1 - Publisher Copyright: © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH
PY - 2022
Y1 - 2022
N2 - The Plk1-interacting checkpoint helicase (PICH) protein localizes to ultrafine anaphase DNA bridges in mitosis along with a complex of DNA repair proteins. Previous studies show PICH deficiency-induced embryonic lethality in mice. However, the function of PICH that is required to suppress embryonic lethality in PICH-deficient mammals remains to be determined. Previous clinical studies suggest a link between PICH deficiency and the onset of acquired aplastic anemia. Here, using Pich knock-out (KO) mouse models, the authors provide evidence for a mechanistic link between PICH deficiency and defective hematopoiesis. Fetal livers from Pich-KO embryos exhibit a significantly elevated number of hematopoietic stem cells (HSCs); however, these HSCs display a higher level of apoptosis and a much-reduced ability to reconstitute a functional hematopoietic system when transplanted into lethally irradiated recipients. Moreover, these HSCs show an elevated cytoplasmic dsDNA expression and an activation of the cGAS-STING pathway, resulting in excessive production of type I interferons (IFN). Importantly, deletion of Ifnar1 or cGAS reverses the defective hematopoiesis. The authors conclude that loss of PICH results in defective hematopoiesis via cGAS-STING-mediated type I IFN production.
AB - The Plk1-interacting checkpoint helicase (PICH) protein localizes to ultrafine anaphase DNA bridges in mitosis along with a complex of DNA repair proteins. Previous studies show PICH deficiency-induced embryonic lethality in mice. However, the function of PICH that is required to suppress embryonic lethality in PICH-deficient mammals remains to be determined. Previous clinical studies suggest a link between PICH deficiency and the onset of acquired aplastic anemia. Here, using Pich knock-out (KO) mouse models, the authors provide evidence for a mechanistic link between PICH deficiency and defective hematopoiesis. Fetal livers from Pich-KO embryos exhibit a significantly elevated number of hematopoietic stem cells (HSCs); however, these HSCs display a higher level of apoptosis and a much-reduced ability to reconstitute a functional hematopoietic system when transplanted into lethally irradiated recipients. Moreover, these HSCs show an elevated cytoplasmic dsDNA expression and an activation of the cGAS-STING pathway, resulting in excessive production of type I interferons (IFN). Importantly, deletion of Ifnar1 or cGAS reverses the defective hematopoiesis. The authors conclude that loss of PICH results in defective hematopoiesis via cGAS-STING-mediated type I IFN production.
U2 - 10.1002/advs.202103837
DO - 10.1002/advs.202103837
M3 - Journal article
C2 - 35037428
AN - SCOPUS:85122735441
VL - 9
JO - Advanced Science
JF - Advanced Science
SN - 2198-3844
IS - 7
M1 - 2103837
ER -
ID: 290523142