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ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis

Author

Listed:
  • Wenqi Chen

    (East China Normal University School of Life Sciences)

  • Jiaxin Wu

    (East China Normal University School of Life Sciences)

  • Peilu She

    (East China Normal University School of Life Sciences
    Southern Medical University)

  • Juan Li

    (East China Normal University School of Life Sciences)

  • Yuying Lan

    (East China Normal University School of Life Sciences)

  • Xueli Hu

    (East China Normal University School of Life Sciences)

  • Yangguo Huangfu

    (East China Normal University School of Life Sciences)

  • Chen Wu

    (Southeast University)

  • Daqing Jin

    (East China Normal University School of Life Sciences)

  • Peng Xie

    (Southeast University)

  • Guanglei Zhuang

    (Shanghai Jiao Tong University)

  • Yuxuan Wu

    (East China Normal University School of Life Sciences)

  • Yiyue Zhang

    (South China University of Technology)

  • Leonard I. Zon

    (Boston Children’s Hospital and Dana-Farber Cancer Institute)

  • Ping Zhu

    (Southern Medical University
    Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention)

  • Tao P. Zhong

    (East China Normal University School of Life Sciences)

Abstract

T lymphocytes, which are essential for cell-mediated immunity in vertebrates, rely on thymic seeding of lymphoid progenitors for commitment, differentiation and maturation. However, the epigenetic programming of lymphoid-primed progenitor migration and differentiation is incompletely understood. Here, we show that zebrafish embryos lacking the epigenetic modulator Atf7ip or Setdb1 methyltransferase exhibit decreased thymic homing and differentiation of lymphoid progenitor cells. We show that Atf7ip regulates T cell progenitor homing and differentiation via Setdb1-triggered H3K9 trimethylation. Atf7ip interacts with Setdb1 to catalyze H3K9me3 modification of the key immune regulator bach2b to derepress the expression of ccr9a and irf4a, thereby promoting lymphoid progenitor homing and intrathymic differentiation. In the absence of Atf7ip or Setdb1, replenishing irf4a or diminishing bach2b restores the thymic trafficking and differentiation of lymphoid progenitor cells. Notably, depletion of ATF7IP by two complementary cre-recombinase alleles in mice (CAG-CreERT2 and Mx1-iCre) impedes the migration of hematopoietic progenitors to the thymus, resulting in declined T lymphopoiesis. These findings establish the role of ATF7IP/SETDB1-mediated epigenetic programming in governing T lymphoid progenitor trafficking and differentiation, with implications for understanding the pathogenesis of human T lymphoid diseases.

Suggested Citation

  • Wenqi Chen & Jiaxin Wu & Peilu She & Juan Li & Yuying Lan & Xueli Hu & Yangguo Huangfu & Chen Wu & Daqing Jin & Peng Xie & Guanglei Zhuang & Yuxuan Wu & Yiyue Zhang & Leonard I. Zon & Ping Zhu & Tao P, 2025. "ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61680-7
    DOI: 10.1038/s41467-025-61680-7
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    1. Zhongzhong Ji & Yaru Sheng & Juju Miao & Xiaoxia Li & Huifang Zhao & Jinming Wang & Chaping Cheng & Xue Wang & Kaiyuan Liu & Kai Zhang & Longmei Xu & Jufang Yao & Lijing Shen & Jian Hou & Wenhao Zhou , 2019. "The histone methyltransferase Setd2 is indispensable for V(D)J recombination," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Shan He & Yongnian Liu & Lijun Meng & Hongxing Sun & Ying Wang & Yun Ji & Janaki Purushe & Pan Chen & Changhong Li & Jozef Madzo & Jean-Pierre Issa & Jonathan Soboloff & Ran Reshef & Bethany Moore & L, 2017. "Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumor immunity," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
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