Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells.
Proc Natl Acad Sci U S A
; 112(32): E4448-57, 2015 Aug 11.
Article
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| MEDLINE
| ID: mdl-26216992
ABSTRACT
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. AireBrd4 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. AireBrd4 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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Timo
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Factores de Transcripción
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Proteínas Nucleares
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Regulación de la Expresión Génica
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Factor B de Elongación Transcripcional Positiva
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Elongación de la Transcripción Genética
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2015
Tipo del documento:
Article