journal contribution posted on 2021-03-31, 05:42 authored by IY Kong, JS Rimes, A Light, I Todorovski, S Jones, E Morand, DA Knight, YE Bergman, SJ Hogg, H Falk, BJ Monahan, PA Stupple, IP Street, Susanne HeinzelSusanne Heinzel, P Bouillet, RW Johnstone, Philip Hodgkin, SJ Vervoort, ED Hawkins
© 2020 The Authors 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.
We thank Professor Steve Nutt, A/Prof. Marnie Blewitt, and A/Prof. Anne Voss for constructive criticism on the manuscript. We would like to thank Lisa Reid, Rhiannan Crawley, and Rebekah Meeny for animal husbandry. J.S.R. was supported by an Australia Postgraduate Award. E.D.H. was supported by a R.D. Wright career development fellowship (1159488) from the National Health and Medical Research Council of Australia (NHMRC) and grants from The Leukemia & Lymphoma Society (6552-18) and NHMRC (1140187 and 1165591). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme Grant 361646. Work from the Johnstone lab (R.W.J.) was supported by the Cancer Council Victoria, the NHMRC, and The Kids' Cancer Project. The Peter MacCallum Foundation and the Australian Cancer Research Foundation provided generous support for equipment and core facilities.
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