The transforming growth factor β (TGF-β) signaling pathway plays important roles in the regulation of tissue homeostasis, immune response, tumorigenesis and early mammalian mesodermal differentiation. It has been reported that TRIM33, as a member of TRIM family, plays a key role in the Nodal signaling pathway and regulates mesendoderm differentiation. The protein levels of TRIM33 had no obvious changed but regulated different groups of genes expression in mouse embryonic stem cells and mesendodermal cells. The mechanism by which TRIM33 functions in different cell context remains unclear.
On Dec/16/2022, Xi Qiaoran's group and Lin Yi's group at Tsinghua University published an online article entitled " Recruitment of TRIM33 to cell-context specific PML nuclear bodies regulates Nodal signaling in mESCs ". In this study, they reported that TRIM33 co-localizes with promyelocytic leukemia nuclear bodies (PML-NBs) specifically in mESCs, to mediate Nodal signaling-directed transcription of Lefty1/2. TRIM33 puncta formation in mESCs depends on PML and on specific assembly of PML-NBs. Moreover, TRIM33 and PML co-regulate Lefty1/2 expression in mESCs, with both PML protein and formation of mESCs-specific PML-NBs being required for TRIM33 recruitment to these loci, and PML-NBs directly associating with the Lefty1/2 loci. Finally, a TurboID proximity-labeling experiment confirmed that TRIM33 is highly enriched only in mESCs-specific PML-NBs. Thus, this study supports a model in which TRIM33 condensates regulate Nodal signaling-directed transcription in mESCs, and shows that PML-NBs can recruit distinct sets of client proteins in a cell-context dependent manner.
Associate Professor Qiaoran Xi and Assistant Professor Yi Lin from School of Life Sciences, Tsinghua University are the co-corresponding authors of this paper. Hongyao Sun and Yutong Chen are co-first authors. Yanqiu Shao from Qiangfeng C. Zhang's lab from the School of Life Sciences at Tsinghua University, contributed to analyze the Hi-C data. Graduated PhD student Dr. Kun Yan from Qiaoran Xi's lab performed RNA-seq and ChIP-seq analyses. This work was supported by NSFC grant, MSTC grant, CLS program and the Tsinghua-IDG/McGovern Institute.
Working model for PML NBs recruitment of TRIM33 on Lefty1/2 transcriptional regulation in mESCs. PML NBs facilitate client protein TRIM33 localization to target gene loci in mESCs, and specifically serve as a hub for transcriptional regulation of Lefty1/2 directed by Nodal signaling.
Link: http://doi.org/10.15252/embj.2022112058
