Regulation of both transcription and RNA turnover contribute to germline specification.
Regulation of both transcription and RNA turnover contribute to germline specification.
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DOI：
10.1093/nar/gkac542
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发表时间：
2022-07-22
影响因子：
14.9
通讯作者：
Wilkinson, Miles F.
中科院分区：
文献类型：
--
作者：
Tan, Kun;Wilkinson, Miles F.
驱动原始生殖细胞 (PGC) 规范的微妙机制仍未完全了解，因为发育中的 PGC 的全基因组转录调控此前仅被间接定义。在这里，我们使用 SLAMseq 分析确定了胚胎干细胞 (ESC) 分化形成外胚层样 (EpiLC) 细胞并最终形成 PGC 样细胞 (PGCLC) 过程中的全基因组转录率。这揭示了数千个基因正在经历转录诱导的爆发和快速关闭，而 RNAseq 分析无法检测到这些基因。我们的 SLAMseq 数据集还允许我们推断 RNA 周转率，这揭示了在 PGCLC 规范期间稳定和不稳定的数千个 mRNA。 mRNA 在 ESC 中往往不稳定，然后随着它们的分化而逐渐稳定。对于某些类别的基因，mRNA 周转调节与转录调节协同作用，但这些过程在基因中以惊人的高频率相互对立。为了测试受调节的 mRNA 周转是否在 PGC 发育中具有生理作用，我们检查了三个受 RNA 周转调节的基因：Sox2、Klf2 和 Ccne1。规避其受调节的 RNA 周转会严重损害 ESC 至 EpiLC 和 EpiLC 至 PGCLC 的转变。我们的研究证明了受调节的 RNA 稳定性在种系发育中的功能重要性，并提供了种系规范过程中转录和转录后调控的路线图。
The nuanced mechanisms driving primordial germ cells (PGC) specification remain incompletely understood since genome-wide transcriptional regulation in developing PGCs has previously only been defined indirectly. Here, using SLAMseq analysis, we determined genome-wide transcription rates during the differentiation of embryonic stem cells (ESCs) to form epiblast-like (EpiLC) cells and ultimately PGC-like cells (PGCLCs). This revealed thousands of genes undergoing bursts of transcriptional induction and rapid shut-off not detectable by RNAseq analysis. Our SLAMseq datasets also allowed us to infer RNA turnover rates, which revealed thousands of mRNAs stabilized and destabilized during PGCLC specification. mRNAs tend to be unstable in ESCs and then are progressively stabilized as they differentiate. For some classes of genes, mRNA turnover regulation collaborates with transcriptional regulation, but these processes oppose each other in a surprisingly high frequency of genes. To test whether regulated mRNA turnover has a physiological role in PGC development, we examined three genes that we found were regulated by RNA turnover: Sox2, Klf2 and Ccne1. Circumvention of their regulated RNA turnover severely impaired the ESC-to-EpiLC and EpiLC-to-PGCLC transitions. Our study demonstrates the functional importance of regulated RNA stability in germline development and provides a roadmap of transcriptional and post-transcriptional regulation during germline specification.
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DOI：
10.1073/pnas.95.9.5082
发表时间：
1998-04-28
影响因子：
11.1
作者：
Arman, E;Haffner-Krausz, R;Lonai, P
通讯作者：
Lonai, P
影响因子：
4.6
作者：
Hoffman, Jackson A.;Wu, Chun-I;Merrill, Bradley J.
通讯作者：
Merrill, Bradley J.
影响因子：
4.5
作者：
Doelken, Lars;Ruzsics, Zsolt;Koszinowski, Ulrich H.
通讯作者：
Koszinowski, Ulrich H.
影响因子：
4.4
作者：
Cheadle, C;Fan, JS;Cho-Chung, YS;Werner, T;Ray, J;Do, L;Gorospe, M;Becker, KG
通讯作者：
Becker, KG
影响因子：
14.9
作者：
Chang CT;Bercovich N;Loh B;Jonas S;Izaurralde E
通讯作者：
Izaurralde E