| Literature DB >> 32193360 |
Omer Gilan1,2, Inmaculada Rioja3, Rab K Prinjha4, Mark A Dawson5,2,6, Kathy Knezevic1, Matthew J Bell3, Miriam M Yeung1, Nicola R Harker3, Enid Y N Lam1,2, Chun-Wa Chung3, Paul Bamborough3, Massimo Petretich7, Marjeta Urh8, Stephen J Atkinson3, Anna K Bassil3, Emma J Roberts3, Dane Vassiliadis1,2, Marian L Burr1,2, Alex G S Preston3, Christopher Wellaway3, Thilo Werner7, James R Gray3, Anne-Marie Michon7, Thomas Gobbetti3, Vinod Kumar9, Peter E Soden3, Andrea Haynes3, Johanna Vappiani7, David F Tough3, Simon Taylor3, Sarah-Jane Dawson1,2,6, Marcus Bantscheff7, Matthew Lindon3, Gerard Drewes7, Emmanuel H Demont3, Danette L Daniels8, Paola Grandi7.
Abstract
The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.Entities:
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Year: 2020 PMID： 32193360 PMCID： PMC7610820 DOI： 10.1126/science.aaz8455
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728