Abstract

Deficiency of the histone H3K9 methyltransferase SETDB1 induces RIPK3-dependent necroptosis in mouse embryonic stem cells (mESCs). However, how necroptosis pathway is activated in this process remains elusive. Here we report that the reactivation of transposable elements (TEs) upon SETDB1 knockout is responsible for the RIPK3 regulation through both cis and trans mechanisms. IAPLTR2_Mm and MMERVK10c-int, both of which are suppressed by SETDB1-dependent H3K9me3, act as enhancer-like cis-regulatory elements and their RIPK3 nearby members enhance RIPK3 expression when SETDB1 is knockout. Moreover, reactivated endogenous retroviruses generate excessive viral mimicry, which promotes necroptosis mainly through Z-DNA-binding protein 1 (ZBP1). These results indicate TEs play an important role in regulating necroptosis.

Details

Title
Transposable elements activation triggers necroptosis in mouse embryonic stem cells
Author
Jin, Lingmei 1 ; He, Jiangping 2 ; Feng, Huijian 3 ; Li, Sa 4 ; Liu, He 5 ; Dong, Hongzhi 6 ; Hu, MingLi 6 ; Huang, Junju 6 ; Wu, Haoyu 6 ; Chen, Jiekai 7 ; Qi, Ling 8 ; Wu, Kaixin 9   VIAFID ORCID Logo 

1  the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Institute of Digestive Disease, Qingyuan, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072); Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China (GRID:grid.428926.3) (ISNI:0000 0004 1798 2725); Guangzhou Regenerative Medicine and Health GuangDong Laboratory, Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou, China (GRID:grid.508040.9) (ISNI:0000 0004 9415 435X) 
2  Guangzhou Regenerative Medicine and Health GuangDong Laboratory, Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou, China (GRID:grid.508040.9) (ISNI:0000 0004 9415 435X); Guangzhou Laboratory, Guangzhou, China (GRID:grid.508040.9) 
3  Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China (GRID:grid.428926.3) (ISNI:0000 0004 1798 2725); Guangzhou Regenerative Medicine and Health GuangDong Laboratory, Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou, China (GRID:grid.508040.9) (ISNI:0000 0004 9415 435X); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
4  Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China (GRID:grid.428926.3) (ISNI:0000 0004 1798 2725); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
5  Guangzhou Regenerative Medicine and Health GuangDong Laboratory, Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou, China (GRID:grid.508040.9) (ISNI:0000 0004 9415 435X) 
6  Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China (GRID:grid.428926.3) (ISNI:0000 0004 1798 2725) 
7  Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China (GRID:grid.428926.3) (ISNI:0000 0004 1798 2725); Guangzhou Regenerative Medicine and Health GuangDong Laboratory, Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou, China (GRID:grid.508040.9) (ISNI:0000 0004 9415 435X); Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Centre for Regenerative Medicine and Health, Hong Kong SAR, China (GRID:grid.9227.e) (ISNI:0000000119573309) 
8  the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Institute of Digestive Disease, Qingyuan, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072) 
9  the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Institute of Digestive Disease, Qingyuan, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072); Guangzhou Regenerative Medicine and Health GuangDong Laboratory, Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou, China (GRID:grid.508040.9) (ISNI:0000 0004 9415 435X); Southern Medical University, Department of Developmental Biology, School of Basic Medical Sciences, Guangzhou, China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471) 
Pages
184
Publication year
2023
Publication date
Mar 2023
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41419-023-05705-3
ProQuest document ID
2794065397
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.