ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis
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 unders...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61680-7 |
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| author | 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. Zhong |
| author_facet | 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. Zhong |
| author_sort | Wenqi Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8cdceaca2f79475ebaea4d47dfe6b347 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8cdceaca2f79475ebaea4d47dfe6b3472025-08-20T03:05:10ZengNature PortfolioNature Communications2041-17232025-07-0116111910.1038/s41467-025-61680-7ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesisWenqi Chen0Jiaxin Wu1Peilu She2Juan Li3Yuying Lan4Xueli Hu5Yangguo Huangfu6Chen Wu7Daqing Jin8Peng Xie9Guanglei Zhuang10Yuxuan Wu11Yiyue Zhang12Leonard I. Zon13Ping Zhu14Tao P. Zhong15Shanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesSEU-ALLEN Joint Center, Institute for Brain and Intelligence, Southeast UniversityShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesSEU-ALLEN Joint Center, Institute for Brain and Intelligence, Southeast UniversityShanghai Key Laboratory of Gynecologic Oncology, School of Medicine, Shanghai Jiao Tong UniversityShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesDivision of Cell, Developmental and Integrative Biology, School of Medicine, South China University of TechnologyStem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital and Dana-Farber Cancer InstituteGuangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityShanghai Key Laboratory of Regulatory Biology, Shanghai Frontier Science Center of Genome Editing and Cell Therapy, East China Normal University School of Life SciencesAbstract 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.https://doi.org/10.1038/s41467-025-61680-7 |
| spellingShingle | 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. Zhong ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis Nature Communications |
| title | ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis |
| title_full | ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis |
| title_fullStr | ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis |
| title_full_unstemmed | ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis |
| title_short | ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis |
| title_sort | atf7ip setdb1 mediated epigenetic programming regulates thymic homing and t lymphopoiesis of hematopoietic progenitors during embryogenesis |
| url | https://doi.org/10.1038/s41467-025-61680-7 |
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