E-GEOD-37270 - BET bromodomain inhibition suppresses TH17-mediated pathology

Status
Released on 20 September 2013, last updated on 30 September 2013
Organism
Mus musculus
Samples (4)
Array (1)
Protocols (7)
Description
IL-17-producing T helper (TH17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine TH17 differentiation from naïve CD4+ T cells, as well as in the activation of previously differentiated TH17 cells. We provide evidence that BET controls TH17 differentiation in a bromodomain-dependent manner through a mechanism that includes the direct regulation of multiple effector TH17-associated cytokines, including IL17, IL21 and GMCSF. We also demonstrate that BET family members Brd2 and Brd4 associate with the Il17 locus in TH17 cells, and that this association requires bromodomains. We recapitulate the critical role of BET bromodomains in TH17 differentiation in vivo and show that therapeutic dosing of the BET inhibitor is efficacious in mouse models of autoimmunity. Our results identify the BET family of proteins as a fundamental link between chromatin signaling and TH17 biology, and support the notion of BET inhibition as a point of therapeutic intervention in autoimmune conditions. 4 samples were analyzed: two conditions in duplicate. Naive T cells were placed in conditions leading to TH17 differentiation, with and without BET inhibitor. RNA was collected at 48 hours.
Experiment type
transcription profiling by array 
Contacts
Barbara M Bryant <barbara.bryant@constellationpharma.com>, Andres Salmeron, Deanna A Mele, Hon-Ren Huang, Jose M Lora, Srimoyee Ghosh
MIAME
PlatformsProtocolsFactorsProcessedRaw
Files
Investigation descriptionE-GEOD-37270.idf.txt
Sample and data relationshipE-GEOD-37270.sdrf.txt
Raw data (1)E-GEOD-37270.raw.1.zip
Processed data (1)E-GEOD-37270.processed.1.zip
Array designA-AFFY-98.adf.txt
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