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CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element

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Listed:
  • Athmane Teghanemt

    (Carver College of Medicine University of Iowa
    Carver College of Medicine University of Iowa)

  • Priyanjali Pulipati

    (Carver College of Medicine University of Iowa
    Carver College of Medicine University of Iowa)

  • Kara Misel-Wuchter

    (Carver College of Medicine University of Iowa
    Molecular Medicine Graduate Program)

  • Kenneth Day

    (Zymo Research Corporation)

  • Matthew S. Yorek

    (Carver College of Medicine University of Iowa
    Carver College of Medicine University of Iowa)

  • Ren Yi

    (New York University)

  • Henry L. Keen

    (University of Iowa)

  • Christy Au

    (New York University School of Medicine)

  • Thorsten Maretzky

    (Carver College of Medicine University of Iowa
    Carver College of Medicine University of Iowa)

  • Prajwal Gurung

    (Carver College of Medicine University of Iowa
    Carver College of Medicine University of Iowa)

  • Dan R. Littman

    (New York University School of Medicine
    Howard Hughes Medical Institute)

  • Priya D. Issuree

    (Carver College of Medicine University of Iowa
    Carver College of Medicine University of Iowa
    Molecular Medicine Graduate Program
    Immunology Graduate Program)

Abstract

The epigenetic patterns that are established during early thymic development might determine mature T cell physiology and function, but the molecular basis and topography of the genetic elements involved are not fully known. Here we show, using the Cd4 locus as a paradigm for early developmental programming, that DNA demethylation during thymic development licenses a novel stimulus-responsive element that is critical for the maintenance of Cd4 gene expression in effector T cells. We document the importance of maintaining high CD4 expression during parasitic infection and show that by driving transcription, this stimulus-responsive element allows for the maintenance of histone H3K4me3 levels during T cell replication, which is critical for preventing de novo DNA methylation at the Cd4 promoter. A failure to undergo epigenetic programming during development leads to gene silencing during effector T cell replication. Our study thus provides evidence of early developmental events shaping the functional fitness of mature effector T cells.

Suggested Citation

  • Athmane Teghanemt & Priyanjali Pulipati & Kara Misel-Wuchter & Kenneth Day & Matthew S. Yorek & Ren Yi & Henry L. Keen & Christy Au & Thorsten Maretzky & Prajwal Gurung & Dan R. Littman & Priya D. Iss, 2022. "CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28914-4
    DOI: 10.1038/s41467-022-28914-4
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    References listed on IDEAS

    as
    1. Xue Guo & Ling Wang & Jie Li & Zhanyu Ding & Jianxiong Xiao & Xiaotong Yin & Shuang He & Pan Shi & Liping Dong & Guohong Li & Changlin Tian & Jiawei Wang & Yao Cong & Yanhui Xu, 2015. "Structural insight into autoinhibition and histone H3-induced activation of DNMT3A," Nature, Nature, vol. 517(7536), pages 640-644, January.
    2. Priya D. Issuree & Kenneth Day & Christy Au & Ramya Raviram & Paul Zappile & Jane A. Skok & Hai-Hui Xue & Richard M. Myers & Dan R. Littman, 2018. "Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    3. Satoshi Kojo & Nighat Yasmin & Sawako Muroi & Mari Tenno & Ichiro Taniuchi, 2018. "Runx-dependent and silencer-independent repression of a maturation enhancer in the Cd4 gene," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
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