The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
Immunol Cell Biol. 2023 Apr;101(4):345-357. doi: 10.1111/imcb.12626. Epub 2023 Feb 14.
The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of Myc. The interactivity of this enhancer coincides with a dramatic, but discrete, spike in Myc expression 3 h post-activation. However, genetic deletion of this region, has little impact on Myc expression, Myc protein level or in vitro and in vivo cell proliferation. Examination of the enhancer deleted regulatory landscape suggests that enhancer redundancy likely sustains Myc expression. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc.
转录因子 Myc 对驱动细胞增殖至关重要，而这一功能在癌症中经常失调。为了避免这种失调，Myc 受到多层次调控的严格控制。其中一个层次是利用远端调控增强子来驱动 Myc 的表达。在这里，我们使用染色体构象捕获技术，在免疫系统 B 细胞激活后的头几个小时内对其进行研究，揭示了 Myc 的一个以前未被识别的增强子。该增强子的相互作用与激活后 3 小时 Myc 表达的显著但离散的尖峰相吻合。然而，该区域的基因缺失对 Myc 的表达、Myc 蛋白水平或体外和体内细胞增殖几乎没有影响。对缺失增强子的调控景观的研究表明，增强子冗余可能维持了 Myc 的表达。这项工作不仅强调了对增强子进行时间上研究的重要性，还强调了像 Myc 这样的关键基因的调控的复杂性和动态性。
