Cell Reports (Oct 2020)
Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation
- Isabella Y. Kong,
- Joel S. Rimes,
- Amanda Light,
- Izabela Todorovski,
- Sarah Jones,
- Eric Morand,
- Deborah A. Knight,
- Ylva E. Bergman,
- Simon J. Hogg,
- Hendrik Falk,
- Brendon J. Monahan,
- Paul A. Stupple,
- Ian P. Street,
- Susanne Heinzel,
- Philippe Bouillet,
- Ricky W. Johnstone,
- Philip D. Hodgkin,
- Stephin J. Vervoort,
- Edwin D. Hawkins
Affiliations
- Isabella Y. Kong
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Joel S. Rimes
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Amanda Light
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Izabela Todorovski
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
- Sarah Jones
- Centre for Inflammatory Diseases, School of Clinical Sciences, Monash University, Parkville, VIC 3052, Australia
- Eric Morand
- Centre for Inflammatory Diseases, School of Clinical Sciences, Monash University, Parkville, VIC 3052, Australia
- Deborah A. Knight
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
- Ylva E. Bergman
- Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
- Simon J. Hogg
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
- Hendrik Falk
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia
- Brendon J. Monahan
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia
- Paul A. Stupple
- Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
- Ian P. Street
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia
- Susanne Heinzel
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Philippe Bouillet
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Ricky W. Johnstone
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
- Philip D. Hodgkin
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
- Stephin J. Vervoort
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia; Corresponding author
- Edwin D. Hawkins
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Corresponding author
- Journal volume & issue
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Vol. 33,
no. 3
p. 108290
Abstract
Summary: JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism that JQ1 targets to elicit changes in antibody production is not understood. Our results show that JQ1 induces apoptosis, reduces cell proliferation, and as a consequence, inhibits antibody-secreting cell differentiation. ChIP-sequencing reveals a selective displacement of Brd4 in response to acute JQ1 treatment (<2 h), resulting in specific transcriptional repression. After 8 h, subsequent alterations in gene expression arise as a result of the global loss of Brd4 occupancy. We demonstrate that apoptosis induced by JQ1 is solely attributed to the pro-apoptotic protein Bim (Bcl2l11). Conversely, cell-cycle regulation by JQ1 is associated with multiple Myc-associated gene targets. Our results demonstrate that JQ1 drives temporal changes in Brd4 displacement that results in a specific transcriptional profile that directly affects B cell survival and proliferation to modulate the humoral immune response.
