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Integrated Methods Redefine Contrasting Mechanisms Governing Foxp3 Induction and Maintenance

77 Pages Posted: 16 Apr 2020 Publication Status: Review Complete

See all articles by Jun Li

Jun Li

St Jude Children’s Research Hospital - Department of Immunology

Beisi Xu

St Jude Children's Research Hospital

Yang Zhang

St Jude Children’s Research Hospital - Department of Tumor Cell Biology

Yiping Fan

St Jude Children’s Research Hospital

Xinying Zong

St Jude Children’s Research Hospital - Department of Immunology

Minghong He

St Jude Children’s Research Hospital - Department of Immunology

Michael Wang

St Jude Children’s Research Hospital - Department of Cell and Molecular Biology

Trevor Cunningham

St Jude Children’s Research Hospital - Department of Immunology

Richard Cross

St Jude Children’s Research Hospital - Department of Immunology

Menglin Jiang

St Jude Children’s Research Hospital - Department of Immunology

Jacob H. Hanna

Weizmann Institute of Science - Department of Molecular Genetics

chunliang li

St Jude Children’s Research Hospital - Department of Tumor Cell Biology

Yongqiang Feng

St Jude Children’s Research Hospital - Department of Immunology

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Abstract

Nuclear factor Foxp3 sustains immune-suppressive function of regulatory T (Treg) cells during their long lifespan, raising a fundamental question about how stochastic Foxp3 induction is transformed into stable Foxp3 expression during Treg lineage commitment. To address this issue, we examined the processes of Treg development and observed an abrupt switch of the transcriptional mechanisms regulating Foxp3 expression. By integrating genetic and pharmacological approaches with unbiased CRISPR screening, we discovered several known and novel nuclear factors spanning a diverse aspects of gene regulation that control Foxp3 induction through a super-additive effect. After Tet-dependent DNA demethylation, Foxp3 transcription was governed by a robust mechanism involving redundant nuclear programs and a shift of Foxp3 enhancers. These distinct regulatory modes transform stochastic induction to a stable state of Foxp3 transcription. Collectively, our results revealed novel regulators and redefined the contrasting mechanisms governing Foxp3 transcription for Treg selection and lineage maintenance.

Keywords: Regulatory T cells, transcription, DNA methylation, nuclear factors, Foxp3, Tet, ascorbic acid

Suggested Citation

Li, Jun and Xu, Beisi and Zhang, Yang and Fan, Yiping and Zong, Xinying and He, Minghong and Wang, Michael and Cunningham, Trevor and Cross, Richard and Jiang, Menglin and Hanna, Jacob H. and li, chunliang and Feng, Yongqiang, Integrated Methods Redefine Contrasting Mechanisms Governing Foxp3 Induction and Maintenance. Available at SSRN: https://ssrn.com/abstract=3577244 or http://dx.doi.org/10.2139/ssrn.3577244
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jun Li

St Jude Children’s Research Hospital - Department of Immunology

United States

Beisi Xu

St Jude Children's Research Hospital ( email )

Memphis, TN 38105
United States

Yang Zhang

St Jude Children’s Research Hospital - Department of Tumor Cell Biology

United States

Yiping Fan

St Jude Children’s Research Hospital ( email )

262 Danny Thomas Place
Memphis,, TN 38105
United States

Xinying Zong

St Jude Children’s Research Hospital - Department of Immunology ( email )

United States

Minghong He

St Jude Children’s Research Hospital - Department of Immunology ( email )

United States

Michael Wang

St Jude Children’s Research Hospital - Department of Cell and Molecular Biology

262 Danny Thomas Place
Memphis, TN 38105
United States

Trevor Cunningham

St Jude Children’s Research Hospital - Department of Immunology ( email )

United States

Richard Cross

St Jude Children’s Research Hospital - Department of Immunology

United States

Menglin Jiang

St Jude Children’s Research Hospital - Department of Immunology ( email )

United States

Jacob H. Hanna

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Chunliang Li

St Jude Children’s Research Hospital - Department of Tumor Cell Biology ( email )

United States

Yongqiang Feng (Contact Author)

St Jude Children’s Research Hospital - Department of Immunology ( email )

United States

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