ESRG is critical to maintain the cell survival and self-renewal/pluripotency of hPSCs by collaborating with MCM2 to suppress p53 pathway

Shasha Li; Hui Liu; Weidong Liu; Ning Shi; Ming Zhao; Siyi Wanggou; Weiren Luo; Lei Wang; Bin Zhu; Xiang Zuo; Wen Xie; Cong Zhao; Yao Zhou; Longlong Luo; Xiang Gao; Xingjun Jiang; Caiping Ren

doi:10.7150/ijbs.79095

ESRG is critical to maintain the cell survival and self-renewal/pluripotency of hPSCs by collaborating with MCM2 to suppress p53 pathway

Int J Biol Sci. 2023 Jan 16;19(3):916-935. doi: 10.7150/ijbs.79095. eCollection 2023.

Authors

Shasha Li^{1

2

3}, Hui Liu⁴, Weidong Liu^{1

2

3}, Ning Shi^{1

2

5}, Ming Zhao^{1

3}, Siyi Wanggou^{1

6}, Weiren Luo⁷, Lei Wang^{1

2

3}, Bin Zhu^{1

2

3}, Xiang Zuo^{1

2

3}, Wen Xie^{1

2

3}, Cong Zhao^{1

2

3}, Yao Zhou^{1

2

3}, Longlong Luo⁵, Xiang Gao⁵, Xingjun Jiang^{1

2

6}, Caiping Ren^{1

2

3}

Affiliations

¹ NHC Key Laboratory of Carcinogenesis, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
³ The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.
⁴ National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
⁵ State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100039, China.
⁶ Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁷ Cancer Research Institute, Shenzhen Third People's Hospital, the Second Affiliated Hospital of Southern University of Science and technology, Shenzhen, Guangdong 518100 China.

Abstract

The mechanisms of self-renewal and pluripotency maintenance of human pluripotent stem cells (hPSCs) have not been fully elucidated, especially for the role of those poorly characterized long noncoding RNAs (lncRNAs). ESRG is a lncRNA highly expressed in hPSCs, and its functional roles are being extensively explored in the field. Here, we identified that the transcription of ESRG can be directly regulated by OCT4, a key self-renewal factor in hPSCs. Knockdown of ESRG induces hPSC differentiation, cell cycle arrest, and apoptosis. ESRG binds to MCM2, a replication-licensing factor, to sustain its steady-state level and nuclear location, safeguarding error-free DNA replication. Further study showed that ESRG knockdown leads to MCM2 abnormalities, resulting in DNA damage and activation of the p53 pathway, ultimately impairs hPSC self-renewal and pluripotency, and induces cell apoptosis. In summary, our study suggests that ESRG, as a novel target of OCT4, plays an essential role in maintaining the cell survival and self-renewal/pluripotency of hPSCs in collaboration with MCM2 to suppress p53 signaling. These findings provide critical insights into the mechanisms underlying the maintenance of self-renewal and pluripotency in hPSCs by lncRNAs.

Keywords: ESRG; MCM2; OCT4; cell survival; human pluripotent stem cells; p53; pluripotency.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / genetics
Cell Survival / genetics
Humans
Minichromosome Maintenance Complex Component 2* / genetics
Minichromosome Maintenance Complex Component 2* / metabolism
Pluripotent Stem Cells* / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Tumor Suppressor Protein p53* / genetics
Tumor Suppressor Protein p53* / metabolism

Substances

MCM2 protein, human
Minichromosome Maintenance Complex Component 2
RNA, Long Noncoding
Tumor Suppressor Protein p53
ESRG lncRNA, human