The EMBO Journal: Revealing a novel mechanism by which PML nucleosomes recruit TRIM33 to regulate gene transcription in mouse embryonic stem cells

The transforming growth factor β β (TGF-β) signaling pathway plays an important role
in tissue homeostasis regulation, immune response, tumorigenesis, and early endodermal differentiation in mammals.
Studies have shown that TRIM33, a member of the TRIM family, is a key member of the TGF-β signaling pathway, regulating the transcription
of relevant marker genes during the differentiation of mouse embryonic stem cells into the mesoderm.
In the course of the study, it was found that there was no significant difference in protein levels of TRIM33 in the differentiation state of mouse embryonic stem cells and mesoderm, but its aggregation state and regulated genes in cells were completely different
.
Therefore, the mechanism of TRIM33 function in different cell states still needs to be studied in depth
.

Xi Qiaoran's research group and Xiaoyi's research group of Tsinghua University published online in The EMBO Journal entitled "Recruitment of TRIM33 to cell-context specific PML nuclear bodies regulates Nodal" in the journal The EMBO Journal Signaling in mESCs).

In this study, it was found for the first time that TRIM33 can specifically form aggregates in mouse embryonic stem cells (mESCs) and co-localize promyelocytic leukemia nucleosomes (PML NBs), and microscopic imaging results show that TRIM33 protein forming aggregates in mESCs are dependent on PML NBs and can only be recruited into PML NBs in specific cell states
.
In addition, genomic and transcriptomic analysis showed that TRIM33 and PML jointly regulate the transcription
of Lefty1/2, a target gene downstream of the Nodel signaling pathway in mESCs 。 In the stem cell state, TRIM33 and PML NBs were co-localized to the target gene Lefty1/2 locus to promote gene transcription.
In the state of embryoid differentiation and oxidative stress, PML NBs left the Lefty1/2 locus, and the TRIM33 aggregates were disaggregated and difficult to bind to the promoter region of the Lefty1/2 gene, resulting in a significant decrease
in the transcription level of the Lefty1/2 gene.
Finally, PML-TurboID proximity label-binding protein profiling confirmed that the protein composition of PML NBs changes dynamically in different cellular environments, and TRIM33 is only highly enriched
in stem cell-specific PML NBs.
Therefore, this study revealed that the transcriptional regulatory center of PML NBs in the formation of mESCs can help TRIM33 form aggregates and regulate Lefty1/2 gene transcription, and demonstrate the regulatory function
of PML NBs as transcriptional regulatory centers to recruit different protein components in a cellular environment-dependent manner.

Associate Professor Xi Qiaoran and Assistant Professor Xiaoyi of the School of Life Sciences, Tsinghua University are co-corresponding authors
of this paper.
Hongyao Sun, a 2016 doctoral student at Tsinghua University, and Yutong Chen, a 2017 doctoral student, are joint first authors
.
Shao Yanqiu, a 2017 doctoral student in Zhang Qiangfeng's research group in the School of Life Sciences of Tsinghua University, helped analyze the Hi-C data
.
Yan Kun, a 2016 doctoral student in Xi Qiaoran's research group, made important contributions
to the smooth development of this work.

This study also thanks to the strong support and help
of Tsinghua University's flow cytometry sorting platform, mass spectrometry analysis platform and imaging platform.
This work has been strongly supported
by the National Natural Science Foundation of China, the National Key Research and Development Program of the Ministry of Science and Technology, the Tsinghua-Peking University Joint Center for Life Sciences, and the Tsinghua-IDG/McGovern Institute of Brain Science.

PML NBs form transcriptional regulatory centers that regulate the transcription of a cluster of genes and recruit TRIM33 and other transcription factors to bind to the Lefty1/2 locus, thereby regulating the transcription
of the Lefty1/2 gene.