Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation

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    Author
    Kong, IY; Rimes, JS; Light, A; Todorovski, I; Jones, S; Morand, E; Knight, DA; Bergman, YE; Hogg, SJ; Falk, H; ...
    Date
    2020-10-20
    Source Title
    Cell Reports
    Publisher
    CELL PRESS
    University of Melbourne Author/s
    Falk, Hendrik; Hawkins, Edwin; Johnstone, Ricky; Monahan, Brendon; Heinzel, Susanne; Vervoort, Stephanus; Hogg, Simon; Bouillet, Philippe; Street, Ian; Hodgkin, Philip; ...
    Affiliation
    Medical Biology (W.E.H.I.)
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    Document Type
    Journal Article
    Citations
    Kong, I. Y., Rimes, J. S., Light, A., Todorovski, I., Jones, S., Morand, E., Knight, D. A., Bergman, Y. E., Hogg, S. J., Falk, H., Monahan, B. J., Stupple, P. A., Street, I. P., Heinzel, S., Bouillet, P., Johnstone, R. W., Hodgkin, P. D., Vervoort, S. J. & Hawkins, E. D. (2020). Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation. CELL REPORTS, 33 (3), https://doi.org/10.1016/j.celrep.2020.108290.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/252630
    DOI
    10.1016/j.celrep.2020.108290
    Abstract
    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.

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