Article | Published:

Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment

Nature Immunology volume 18, pages 173183 (2017) | Download Citation

  • An Erratum to this article was published on 22 March 2017
  • An Addendum to this article was published on 18 October 2017

This article has been updated

Abstract

Most Foxp3+ regulatory T (Treg) cells develop in the thymus as a functionally mature T cell subpopulation specialized for immune suppression. Their cell fate appears to be determined before Foxp3 expression; yet molecular events that prime Foxp3 Treg precursor cells are largely obscure. We found that Treg cell–specific super-enhancers (Treg-SEs), which were associated with Foxp3 and other Treg cell signature genes, began to be activated in Treg precursor cells. T cell–specific deficiency of the genome organizer Satb1 impaired Treg-SE activation and the subsequent expression of Treg signature genes, causing severe autoimmunity due to Treg cell deficiency. These results suggest that Satb1-dependent Treg-SE activation is crucial for Treg cell lineage specification in the thymus and that its perturbation is causative of autoimmune and other immunological diseases.

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Change history

  • 23 January 2017

    In the version of this article initially published, the labels above the plots in Figure 4b were incorrect (with 'Open chromatin' above the first two columns and 'Closed chromatin' above the second two columns). The correct labeling is 'Open chromatin' above the first column, 'Closed chromatin' above the second column, 'Open chromatin' above the third column and 'Closed chromatin' above the fourth column. The error has been corrected in the HTML and PDF versions of the article.

  • 17 April 2017

    ChIP-seq, RNA-seq, MBD-seq and ATAC-seq data sets associated with this article were originally deposited in the DNA Data Bank of Japan under accession numbers DRA003955, DRA004738 and DRA005202. The sequencing data sets have now also been submitted to the NCBI SRA database. The SRA accession number is DRP003376, and all the data (109 samples in total) are accessible at https://www.ncbi.nlm.nih.gov/sra/?term=DRP003376.

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Acknowledgements

We thank Y. Nakamura for DNA sequencing support and assistance with RNA-seq experiments, S. Kojo for providing technical advice regarding ChIP-seq experiments, and K. Chen for reading the manuscript. Bioinformatics analyses were conducted using the computer system at the Genome Information Research Center of the Research Institute for Microbial Diseases at Osaka University. This work was supported by Grants-in-Aid for Japanese Society for the Promotion of Science (JSPS) Fellows 261560 from the JSPS to Y.K. and Core Research for Evolutional Science and Technology from the Japan Science and Technology Agency to S.S. and JSPS Grants-in-Aid for Scientific Research B 15H04744 to N.O.

Author information

Affiliations

  1. Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.

    • Yohko Kitagawa
    • , Naganari Ohkura
    • , Yujiro Kidani
    • , Keiji Hirota
    • , Ryoji Kawakami
    • , Keiko Yasuda
    •  & Shimon Sakaguchi
  2. Laboratory of Experimental Immunology, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

    • Yohko Kitagawa
    • , Keiko Yasuda
    •  & Shimon Sakaguchi
  3. Immuno-Genomics Research Unit, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.

    • Alexis Vandenbon
  4. Laboratory of Integrative Biological Science, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

    • Keiji Hirota
  5. Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.

    • Daisuke Motooka
    •  & Shota Nakamura
  6. Department of Molecular Immunology, School of Medicine, Toho University, Tokyo, Japan.

    • Motonari Kondo
  7. Laboratory for Transcriptional Regulation, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.

    • Ichiro Taniuchi
  8. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.

    • Terumi Kohwi-Shigematsu

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Contributions

Y. Kitagawa designed, performed and analyzed most experiments, including flow cytometric analyses, in vivo and in vitro experiments, ChIP-seq, library preparation for sequencing and bioinformatics analyses. N.O. performed ATAC-seq and MBD-seq, Y. Kidani assisted with bioinformatical analyses and performed immunoblotting. A.V. and K.H. provided crucial advice. R.K. performed H3K4me3 ChIP-seq. K.Y. assisted with histological analysis. D.M. and S.N. performed amplicon sequencing. I.T. and T.K.-S. provided helpful suggestions. T.K.-S. and M.K. provided Satb1 conditional knockout mouse. I.T. provided Thpok-Cre mouse. Y. Kitagawa and S.S. wrote the manuscript, and all authors reviewed it. T.K.-S. and N.O. critically read the manuscript and provided advice. S.S. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shimon Sakaguchi.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8

Excel files

  1. 1.

    Supplementary Data Set

    Treg-SEs, Tconv-SEs and their associated gene list.

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DOI

https://doi.org/10.1038/ni.3646