Kong Isabella Y, Rimes Joel S, Light Amanda, Todorovski Izabela, Jones Sarah, Morand Eric, Knight Deborah A, Bergman Ylva E, Hogg Simon J, Falk Hendrik, Monahan Brendon J, Stupple Paul A, Street Ian P, Heinzel Susanne, Bouillet Philippe, Johnstone Ricky W, Hodgkin Philip D, Vervoort Stephin J, Hawkins Edwin D
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.
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.
Cell Rep. 2020 Oct 20;33(3):108290. doi: 10.1016/j.celrep.2020.108290.
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.
JQ1是一种具有免疫调节作用的BET溴结构域抑制剂。然而，JQ1引发抗体产生变化所靶向的精确分子机制尚不清楚。我们的结果表明，JQ1诱导细胞凋亡，减少细胞增殖，进而抑制抗体分泌细胞的分化。染色质免疫沉淀测序显示，急性JQ1处理（<2小时）后，Brd4发生选择性移位，导致特异性转录抑制。8小时后，由于Brd4占据的整体丧失，基因表达随后出现改变。我们证明，JQ1诱导的细胞凋亡完全归因于促凋亡蛋白Bim（Bcl2l11）。相反，JQ1对细胞周期的调节与多个Myc相关基因靶点有关。我们的结果表明，JQ1驱动Brd4移位的时间变化，导致特定的转录谱，直接影响B细胞存活和增殖，从而调节体液免疫反应。
