Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Yoshida Hideyuki; Bansal Kushagra; Schaefer UweChapman TrevorRioja InmaculadaProekt IrinaAnderson Mark S.Prinjha Rab K.Tarakhovsky AlexanderBenoist ChristopheMathis Diane

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Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

机译：Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

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摘要

Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomain-containing protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire: Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire: Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2015年第32期|E4448-E4457|共10页
作者
Yoshida Hideyuki; Bansal Kushagra; Schaefer UweChapman TrevorRioja InmaculadaProekt IrinaAnderson Mark S.Prinjha Rab K.Tarakhovsky AlexanderBenoist ChristopheMathis Diane;
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作者单位

Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA;

Rockefeller Univ, Lab Immune Cell Epigenet & Signaling, New York, NY 10065 USA;

GlaxoSmithKline, Med Res Ctr, Immunoinflammat Therapy Area, Epinova Discovery Performance Unit, Stevenage SG1 2NY, Herts, EnglandUniv Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USAUniv Calif San Francisco, Diabet Ctr, San Francisco, CA 94143 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
immunological tolerance; thymus; Aire; bromodomain protein; transcriptional elongation;

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

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