Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA.
Nature. 2020 Mar;579(7797):136-140. doi: 10.1038/s41586-020-2034-1. Epub 2020 Feb 19.
Metazoan development requires the robust proliferation of progenitor cells, the identities of which are established by tightly controlled transcriptional networks. As gene expression is globally inhibited during mitosis, the transcriptional programs that define cell identity must be restarted in each cell cycle but how this is accomplished is poorly understood. Here we identify a ubiquitin-dependent mechanism that integrates gene expression with cell division to preserve cell identity. We found that WDR5 and TBP, which bind active interphase promoters, recruit the anaphase-promoting complex (APC/C) to specific transcription start sites during mitosis. This allows APC/C to decorate histones with ubiquitin chains branched at Lys11 and Lys48 (K11/K48-branched ubiquitin chains) that recruit p97 (also known as VCP) and the proteasome, which ensures the rapid expression of pluripotency genes in the next cell cycle. Mitotic exit and the re-initiation of transcription are thus controlled by a single regulator (APC/C), which provides a robust mechanism for maintaining cell identity throughout cell division.
后生动物的发育需要祖细胞的大量增殖，而祖细胞的身份是由严格控制的转录网络决定的。由于有丝分裂期间基因表达被全局抑制，因此必须在每个细胞周期中重新启动定义细胞身份的转录程序，但这是如何完成的还知之甚少。在这里，我们发现了一种泛素依赖性机制，它将基因表达与细胞分裂整合在一起，以维持细胞身份。我们发现，与活性间期间期启动子结合的 WDR5 和 TBP 在有丝分裂期间将后期促进复合物 (APC/C) 招募到特定的转录起始位点。这使得 APC/C 能够用 Lys11 和 Lys48 分支的泛素链（K11/K48 分支泛素链）修饰组蛋白，招募 p97（也称为 VCP）和蛋白酶体，从而确保在下一个细胞周期中快速表达多能性基因。因此，有丝分裂退出和转录的重新启动受到单个调节因子（APC/C）的控制，这为整个细胞分裂过程中维持细胞身份提供了一个强大的机制。
