Lab of Pathology, National Cancer Institutes, Bethesda, MD, USA.
Lab of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institutes, Bethesda, MD, USA.
Commun Biol. 2020 Oct 1;3(1):545. doi: 10.1038/s42003-020-01264-x.
Physiologically, MYC levels must be precisely set to faithfully amplify the transcriptome, but in cancer MYC is quantitatively misregulated. Here, we study the variation of MYC amongst single primary cells (B-cells and murine embryonic fibroblasts, MEFs) for the repercussions of variable cellular MYC-levels and setpoints. Because FUBPs have been proposed to be molecular "cruise controls" that constrain MYC expression, their role in determining basal or activated MYC-levels was also examined. Growing cells remember low and high-MYC setpoints through multiple cell divisions and are limited by the same expression ceiling even after modest MYC-activation. High MYC MEFs are enriched for mRNAs regulating inflammation and immunity. After strong stimulation, many cells break through the ceiling and intensify MYC expression. Lacking FUBPs, unstimulated MEFs express levels otherwise attained only with stimulation and sponsor MYC chromatin changes, revealed by chromatin marks. Thus, the FUBPs enforce epigenetic setpoints that restrict MYC expression.
从生理学角度来看，MYC 水平必须精确设定，以忠实地放大转录组，但在癌症中，MYC 被定量失调。在这里，我们研究了单个原代细胞（B 细胞和小鼠胚胎成纤维细胞，MEFs）中 MYC 的变化，以研究细胞内 MYC 水平和设定点的变化所带来的影响。因为已经提出 FUBPs 是限制 MYC 表达的分子“巡航控制”，所以我们还研究了它们在确定基础或激活的 MYC 水平方面的作用。生长中的细胞通过多次细胞分裂记住低和高 MYC 设定点，并且即使在适度的 MYC 激活后，也受到相同的表达上限的限制。高 MYC MEFs 富含调节炎症和免疫的 mRNA。经过强烈刺激后，许多细胞突破上限并加剧 MYC 表达。缺乏 FUBPs 的情况下，未受刺激的 MEFs 表达的水平只有在受到刺激和赞助 MYC 染色质变化后才能达到，这可以通过染色质标记来揭示。因此，FUBPs 执行限制 MYC 表达的表观遗传设定点。
