IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33733-8.html
   My bibliography  Save this article

Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation

Author

Listed:
  • Sang-A Park

    (National Institutes of Health)

  • Yun-Ji Lim

    (National Institutes of Health)

  • Wai Lim Ku

    (National Institutes of Health)

  • Dunfang Zhang

    (National Institutes of Health)

  • Kairong Cui

    (National Institutes of Health)

  • Liu-Ya Tang

    (National Institutes of Health)

  • Cheryl Chia

    (National Institutes of Health)

  • Peter Zanvit

    (National Institutes of Health)

  • Zuojia Chen

    (National Institutes of Health)

  • Wenwen Jin

    (National Institutes of Health)

  • Dandan Wang

    (National Institutes of Health)

  • Junji Xu

    (National Institutes of Health)

  • Ousheng Liu

    (National Institutes of Health)

  • Fu Wang

    (National Institutes of Health)

  • Alexander Cain

    (National Institutes of Health)

  • Nancy Guo

    (National Institutes of Health)

  • Hiroko Nakatsukasa

    (National Institutes of Health)

  • Chuan Wu

    (National Institutes of Health)

  • Ying E. Zhang

    (National Institutes of Health)

  • Keji Zhao

    (National Institutes of Health)

  • WanJun Chen

    (National Institutes of Health)

Abstract

Interleukin-9 (IL-9)-producing CD4+ T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-β), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-β and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser213) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser213. Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.

Suggested Citation

  • Sang-A Park & Yun-Ji Lim & Wai Lim Ku & Dunfang Zhang & Kairong Cui & Liu-Ya Tang & Cheryl Chia & Peter Zanvit & Zuojia Chen & Wenwen Jin & Dandan Wang & Junji Xu & Ousheng Liu & Fu Wang & Alexander C, 2022. "Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33733-8
    DOI: 10.1038/s41467-022-33733-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33733-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33733-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Julio Gomez-Rodriguez & Françoise Meylan & Robin Handon & Erika T. Hayes & Stacie M. Anderson & Martha R. Kirby & Richard M. Siegel & Pamela L. Schwartzberg, 2016. "Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
    2. Wenfei Jin & Qingsong Tang & Mimi Wan & Kairong Cui & Yi Zhang & Gang Ren & Bing Ni & Jeffrey Sklar & Teresa M. Przytycka & Richard Childs & David Levens & Keji Zhao, 2015. "Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples," Nature, Nature, vol. 528(7580), pages 142-146, December.
    3. Gang Xue & Guangxu Jin & Jing Fang & Yong Lu, 2019. "IL-4 together with IL-1β induces antitumor Th9 cell differentiation in the absence of TGF-β signaling," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    4. Yongyao Fu & Jocelyn Wang & Gayathri Panangipalli & Benjamin J. Ulrich & Byunghee Koh & Chengxian Xu & Rakshin Kharwadkar & Xiaona Chu & Yue Wang & Hongyu Gao & Wenting Wu & Jie Sun & Robert S. Tepper, 2020. "STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    5. Isao Matsuura & Natalia G. Denissova & Guannan Wang & Dongming He & Jianyin Long & Fang Liu, 2004. "Cyclin-dependent kinases regulate the antiproliferative function of Smads," Nature, Nature, vol. 430(6996), pages 226-231, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Qiang Shan & Xiang Li & Xia Chen & Zhouhao Zeng & Shaoqi Zhu & Kexin Gai & Weiqun Peng & Hai-Hui Xue, 2021. "Tcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    2. Steven Henikoff & Jorja G. Henikoff & Kami Ahmad & Ronald M. Paranal & Derek H. Janssens & Zachary R. Russell & Frank Szulzewsky & Sita Kugel & Eric C. Holland, 2023. "Epigenomic analysis of formalin-fixed paraffin-embedded samples by CUT&Tag," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Yongyao Fu & Abigail Pajulas & Jocelyn Wang & Baohua Zhou & Anthony Cannon & Cherry Cheuk Lam Cheung & Jilu Zhang & Huaxin Zhou & Amanda Jo Fisher & David T. Omstead & Sabrina Khan & Lei Han & Jean-Ch, 2022. "Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Gang Ren & Wai Lim Ku & Guangzhe Ge & Jackson A. Hoffman & Jee Youn Kang & Qingsong Tang & Kairong Cui & Yong He & Yukun Guan & Bin Gao & Chengyu Liu & Trevor K. Archer & Keji Zhao, 2024. "Acute depletion of BRG1 reveals its primary function as an activator of transcription," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Youtao Lu & Jaehee Lee & Jifen Li & Srinivasa Rao Allu & Jinhui Wang & HyunBum Kim & Kevin L. Bullaughey & Stephen A. Fisher & C. Erik Nordgren & Jean G. Rosario & Stewart A. Anderson & Alexandra V. U, 2023. "CHEX-seq detects single-cell genomic single-stranded DNA with catalytical potential," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Jiawei Zhang & Yichao Gan & Hongzhi Li & Jie Yin & Xin He & Liming Lin & Senlin Xu & Zhipeng Fang & Byung-wook Kim & Lina Gao & Lili Ding & Eryun Zhang & Xiaoxiao Ma & Junfeng Li & Ling Li & Yang Xu &, 2022. "Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Alan Yue Yang Teo & Jordan W. Squair & Gregoire Courtine & Michael A. Skinnider, 2024. "Best practices for differential accessibility analysis in single-cell epigenomics," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33733-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.