Article abstract
Nature Immunology 9, 1113 - 1121 (2008)
Published online: 7 September 2008 | doi:10.1038/ni.1650
Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate
Sawako Muroi1,2, Yoshinori Naoe1, Chizuko Miyamoto1, Kaori Akiyama1, Tomokatsu Ikawa3, Kyoko Masuda3,4, Hiroshi Kawamoto3 & Ichiro Taniuchi1,2
Abstract
CD4 and the transcription factor ThPOK are essential for the differentiation of major histocompatibility complex class II–restricted thymocytes into the helper T cell lineage; their genes (Cd4 and Zbtb7b (called 'ThPOK' here)) are repressed by transcriptional silencer elements in cytotoxic T cells. The molecular mechanisms regulating expression of these genes during helper T cell lineage differentiation remain unknown. Here we showed that inefficient upregulation of ThPOK, induced by removal of the proximal enhancer from the ThPOK locus, resulted in the transdifferentiation of helper lineage–specified cells into the cytotoxic T cell lineage. Furthermore, direct antagonism by ThPOK of the Cd4 and ThPOK silencers generated two regulatory loops that initially inhibited Cd4 downregulation and later stabilized ThPOK expression. Our results show how an initial lineage–specification signal can be amplified and stabilized during the lineage–commitment process.
- Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
- Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
- Laboratory for Lymphocyte Development, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
- Present address: Department of Genetics, University of Georgia, Athens, Georgia 30602, USA.
Correspondence to: Ichiro Taniuchi1,2 e-mail: taniuchi@rcai.riken.jp
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