Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation

Marc Beyer; Yasser Thabet; Roman Ulrich Müller; Timothy Sadlon; Sabine Classen; Katharina Lahl; Samik Basu; Xuyu Zhou; Samantha L. Bailey-Bucktrout; Wolfgang Krebs; Eva A. Schönfeld; Jan Böttcher; Tatiana Golovina; Christian T. Mayer; Andrea Hofmann; Daniel Sommer; Svenja Debey-Pascher; Elmar Endl; Andreas Limmer; Keli L. Hippen; Bruce R. Blazar; Robert Balderas; Thomas Quast; Andreas Waha; Günter Mayer; Michael Famulok; Percy A. Knolle; Claudia Wickenhauser; Waldemar Kolanus; Bernhard Schermer; Jeffrey A. Bluestone; Simon C. Barry; Tim Sparwasser; James L. Riley; Joachim L. Schultze

doi:10.1038/ni.2084

Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation

Marc Beyer, Yasser Thabet, Roman Ulrich Müller, Timothy Sadlon, Sabine Classen, Katharina Lahl, Samik Basu, Xuyu Zhou, Samantha L. Bailey-Bucktrout, Wolfgang Krebs, Eva A. Schönfeld, Jan Böttcher, Tatiana Golovina, Christian T. Mayer, Andrea Hofmann, Daniel Sommer, Svenja Debey-Pascher, Elmar Endl, Andreas Limmer, Keli L. HippenBruce R. Blazar, Robert Balderas, Thomas Quast, Andreas Waha, Günter Mayer, Michael Famulok, Percy A. Knolle, Claudia Wickenhauser, Waldemar Kolanus, Bernhard Schermer, Jeffrey A. Bluestone, Simon C. Barry, Tim Sparwasser, James L. Riley, Joachim L. Schultze

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Abstract

Regulatory T cells (T reg cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T eff cell) function and gain of suppressive activity by T reg cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T reg cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3ĝ€2 untranslated region. Release of SATB1 from the control of Foxp3 in T reg cells caused loss of suppressive function, establishment of transcriptional T eff cell programs and induction of T eff cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T reg cell functionality.

Original language	English (US)
Pages (from-to)	898-907
Number of pages	10
Journal	Nature immunology
Volume	12
Issue number	9
DOIs	https://doi.org/10.1038/ni.2084
State	Published - Sep 2011

Bibliographical note

Funding Information:
We thank M. Mai, M. Kraut, S. Keller, N. Kuhn, J. Birke, I. Büchmann, A. Dolf and P. Wurst for technical assistance; M. Hoch, M. Pankratz, S. Burgdorf, A. Popov and A. Staratschek-Jox, as well as all other laboratory members, for discussions; and J. Oldenburg for blood samples from healthy subjects. Supported by the German Research Foundation (Sonderforschungsbereich 832, SFB 704, INST 217/576-1 and INST 217/577-1 to J.L.S. and M.B.), the Wilhelm-Sander-Foundation (J.L.S. and M.B.), the German Cancer Aid (J.L.S.), the German Jose-Carreras-Foundation (J.L.S. and M.B.), the Federal Ministry of Education and Research (Nationale Genomforschungsnetz 2 to J.L.S.), the Humboldt Foundation (J.L.S.), the Leukemia and Lymphoma Society of America (R6029-07 to B.R.B. and K.L.H.), the Juvenile Diabetes Research Foundation (16-2008-643 to X.Z., S.L.B.-B. and J.A.B.), the University of California, San Francisco, Autoimmunity Center of Excellence (X.Z., S.L.B.-B. and J.A.B.), the National Health and Medical Research Council (339123, 565314 to S.C.B.), the German Research Foundation (SCHE 1562 and

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Beyer, M., Thabet, Y., Müller, R. U., Sadlon, T., Classen, S., Lahl, K., Basu, S., Zhou, X., Bailey-Bucktrout, S. L., Krebs, W., Schönfeld, E. A., Böttcher, J., Golovina, T., Mayer, C. T., Hofmann, A., Sommer, D., Debey-Pascher, S., Endl, E., Limmer, A., ... Schultze, J. L. (2011). Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nature immunology, 12(9), 898-907. https://doi.org/10.1038/ni.2084

Beyer, M, Thabet, Y, Müller, RU, Sadlon, T, Classen, S, Lahl, K, Basu, S, Zhou, X, Bailey-Bucktrout, SL, Krebs, W, Schönfeld, EA, Böttcher, J, Golovina, T, Mayer, CT, Hofmann, A, Sommer, D, Debey-Pascher, S, Endl, E, Limmer, A, Hippen, KL , Blazar, BR, Balderas, R, Quast, T, Waha, A, Mayer, G, Famulok, M, Knolle, PA, Wickenhauser, C, Kolanus, W, Schermer, B, Bluestone, JA, Barry, SC, Sparwasser, T, Riley, JL & Schultze, JL 2011, 'Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation', Nature immunology, vol. 12, no. 9, pp. 898-907. https://doi.org/10.1038/ni.2084

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title = "Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation",

abstract = "Regulatory T cells (T reg cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T eff cell) function and gain of suppressive activity by T reg cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T reg cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3ĝ€2 untranslated region. Release of SATB1 from the control of Foxp3 in T reg cells caused loss of suppressive function, establishment of transcriptional T eff cell programs and induction of T eff cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T reg cell functionality.",

author = "Marc Beyer and Yasser Thabet and M{\"u}ller, {Roman Ulrich} and Timothy Sadlon and Sabine Classen and Katharina Lahl and Samik Basu and Xuyu Zhou and Bailey-Bucktrout, {Samantha L.} and Wolfgang Krebs and Sch{\"o}nfeld, {Eva A.} and Jan B{\"o}ttcher and Tatiana Golovina and Mayer, {Christian T.} and Andrea Hofmann and Daniel Sommer and Svenja Debey-Pascher and Elmar Endl and Andreas Limmer and Hippen, {Keli L.} and Blazar, {Bruce R.} and Robert Balderas and Thomas Quast and Andreas Waha and G{\"u}nter Mayer and Michael Famulok and Knolle, {Percy A.} and Claudia Wickenhauser and Waldemar Kolanus and Bernhard Schermer and Bluestone, {Jeffrey A.} and Barry, {Simon C.} and Tim Sparwasser and Riley, {James L.} and Schultze, {Joachim L.}",

note = "Funding Information: We thank M. Mai, M. Kraut, S. Keller, N. Kuhn, J. Birke, I. B{\"u}chmann, A. Dolf and P. Wurst for technical assistance; M. Hoch, M. Pankratz, S. Burgdorf, A. Popov and A. Staratschek-Jox, as well as all other laboratory members, for discussions; and J. Oldenburg for blood samples from healthy subjects. Supported by the German Research Foundation (Sonderforschungsbereich 832, SFB 704, INST 217/576-1 and INST 217/577-1 to J.L.S. and M.B.), the Wilhelm-Sander-Foundation (J.L.S. and M.B.), the German Cancer Aid (J.L.S.), the German Jose-Carreras-Foundation (J.L.S. and M.B.), the Federal Ministry of Education and Research (Nationale Genomforschungsnetz 2 to J.L.S.), the Humboldt Foundation (J.L.S.), the Leukemia and Lymphoma Society of America (R6029-07 to B.R.B. and K.L.H.), the Juvenile Diabetes Research Foundation (16-2008-643 to X.Z., S.L.B.-B. and J.A.B.), the University of California, San Francisco, Autoimmunity Center of Excellence (X.Z., S.L.B.-B. and J.A.B.), the National Health and Medical Research Council (339123, 565314 to S.C.B.), the German Research Foundation (SCHE 1562 and",

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T1 - Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation

AU - Beyer, Marc

AU - Thabet, Yasser

AU - Müller, Roman Ulrich

AU - Sadlon, Timothy

AU - Classen, Sabine

AU - Lahl, Katharina

AU - Basu, Samik

AU - Zhou, Xuyu

AU - Bailey-Bucktrout, Samantha L.

AU - Krebs, Wolfgang

AU - Schönfeld, Eva A.

AU - Böttcher, Jan

AU - Golovina, Tatiana

AU - Mayer, Christian T.

AU - Hofmann, Andrea

AU - Sommer, Daniel

AU - Debey-Pascher, Svenja

AU - Endl, Elmar

AU - Limmer, Andreas

AU - Hippen, Keli L.

AU - Blazar, Bruce R.

AU - Balderas, Robert

AU - Quast, Thomas

AU - Waha, Andreas

AU - Mayer, Günter

AU - Famulok, Michael

AU - Knolle, Percy A.

AU - Wickenhauser, Claudia

AU - Kolanus, Waldemar

AU - Schermer, Bernhard

AU - Bluestone, Jeffrey A.

AU - Barry, Simon C.

AU - Sparwasser, Tim

AU - Riley, James L.

AU - Schultze, Joachim L.

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N2 - Regulatory T cells (T reg cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T eff cell) function and gain of suppressive activity by T reg cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T reg cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3ĝ€2 untranslated region. Release of SATB1 from the control of Foxp3 in T reg cells caused loss of suppressive function, establishment of transcriptional T eff cell programs and induction of T eff cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T reg cell functionality.

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Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation

Abstract

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