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OCT4 maintains self-renewal and reverses senescence in human hair follicle mesenchymal stem cells through the downregulation of p21 by DNA methyltransferases.
Stem Cell Res Ther. 2019 01 15; 10(1):28.SC

Abstract

BACKGROUND

Self-renewal is dependent on an intrinsic gene regulatory network centered on OCT4 and on an atypical cell cycle G1/S transition, which is also regulated by OCT4. p21, a gene negatively associated with self-renewal and a senescence marker, is a member of the universal cyclin-dependent kinase inhibitors (CDKIs) and plays critical roles in the regulation of the G1/S transition. The expression of p21 can be regulated by OCT4-targeted DNA methyltransferases (DNMTs), which play distinct roles in gene regulation and maintaining pluripotency properties. The aim of this study was to determine the role of OCT4 in the regulation of self-renewal and senescence in human hair follicle mesenchymal stem cells (hHFMSCs) and to characterize the molecular mechanisms involved.

METHODS

A lentiviral vector was used to ectopically express OCT4. The influences of OCT4 on the self-renewal and senescence of hHFMSCs were investigated. Next-generation sequencing (NGS) was performed to identify the downstream genes of OCT4 in this process. Methylation-specific PCR (MSP) analysis was performed to measure the methylation level of the p21 promoter region. p21 was overexpressed in hHFMSCsOCT4 to test its downstream effect on OCT4. The regulatory effect of OCT4 on DNMTs was examined by ChIP assay. 5-aza-dC/zebularine was used to inhibit the expression of DNMTs, and then self-renewal properties and senescence in hHFMSCs were detected.

RESULTS

The overexpression of OCT4 promoted proliferation, cell cycle progression, and osteogenic differentiation capacity of hHFMSCs. The cell senescence of hHFMSCs was markedly suppressed due to the ectopic expression of OCT4. Through NGS, we identified 2466 differentially expressed genes (DEGs) between hHFMSCsOCT4 and hHFMSCsEGFP, including p21, which was downregulated. The overexpression of p21 abrogated the proliferation and osteogenic differentiation capacity of hHFMSCsOCT4 and promoted cell senescence. OCT4 enhanced the transcription of DNMT genes, leading to an elevation in the methylation of the p21 promoter. The inhibition of DNMTs reversed the OCT4-induced p21 reduction, depleted the self-renewal of hHFMSCsOCT4, and triggered cell senescence.

CONCLUSIONS

OCT4 maintains the self-renewal ability of hHFMSCs and reverses senescence by suppressing the expression of p21 through the upregulation of DNMTs.

Authors+Show Affiliations

The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.Cell Processing Section, Department of Transfusion, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.Department of Cellular and Molecular Medicine, University of California, San Diego, CA, 92093-0651, USA.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China. quancs1@163.com.

Pub Type(s)

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

Language

eng

PubMed ID

30646941

Citation

Lu, Yan, et al. "OCT4 Maintains Self-renewal and Reverses Senescence in Human Hair Follicle Mesenchymal Stem Cells Through the Downregulation of P21 By DNA Methyltransferases." Stem Cell Research & Therapy, vol. 10, no. 1, 2019, p. 28.
Lu Y, Qu H, Qi D, et al. OCT4 maintains self-renewal and reverses senescence in human hair follicle mesenchymal stem cells through the downregulation of p21 by DNA methyltransferases. Stem Cell Res Ther. 2019;10(1):28.
Lu, Y., Qu, H., Qi, D., Xu, W., Liu, S., Jin, X., Song, P., Guo, Y., Jia, Y., Wang, X., Li, H., Li, Y., & Quan, C. (2019). OCT4 maintains self-renewal and reverses senescence in human hair follicle mesenchymal stem cells through the downregulation of p21 by DNA methyltransferases. Stem Cell Research & Therapy, 10(1), 28. https://doi.org/10.1186/s13287-018-1120-x
Lu Y, et al. OCT4 Maintains Self-renewal and Reverses Senescence in Human Hair Follicle Mesenchymal Stem Cells Through the Downregulation of P21 By DNA Methyltransferases. Stem Cell Res Ther. 2019 01 15;10(1):28. PubMed PMID: 30646941.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - OCT4 maintains self-renewal and reverses senescence in human hair follicle mesenchymal stem cells through the downregulation of p21 by DNA methyltransferases. AU - Lu,Yan, AU - Qu,Huinan, AU - Qi,Da, AU - Xu,Wenhong, AU - Liu,Shutong, AU - Jin,Xiangshu, AU - Song,Peiye, AU - Guo,Yantong, AU - Jia,Yiyang, AU - Wang,Xinqi, AU - Li,Hairi, AU - Li,Yulin, AU - Quan,Chengshi, Y1 - 2019/01/15/ PY - 2018/08/26/received PY - 2018/12/20/accepted PY - 2018/12/11/revised PY - 2019/1/17/entrez PY - 2019/1/17/pubmed PY - 2019/1/17/medline KW - DNMTs KW - OCT4 KW - Self-renewal KW - Senescence KW - hHFMSCs KW - p21 SP - 28 EP - 28 JF - Stem cell research & therapy JO - Stem Cell Res Ther VL - 10 IS - 1 N2 - BACKGROUND: Self-renewal is dependent on an intrinsic gene regulatory network centered on OCT4 and on an atypical cell cycle G1/S transition, which is also regulated by OCT4. p21, a gene negatively associated with self-renewal and a senescence marker, is a member of the universal cyclin-dependent kinase inhibitors (CDKIs) and plays critical roles in the regulation of the G1/S transition. The expression of p21 can be regulated by OCT4-targeted DNA methyltransferases (DNMTs), which play distinct roles in gene regulation and maintaining pluripotency properties. The aim of this study was to determine the role of OCT4 in the regulation of self-renewal and senescence in human hair follicle mesenchymal stem cells (hHFMSCs) and to characterize the molecular mechanisms involved. METHODS: A lentiviral vector was used to ectopically express OCT4. The influences of OCT4 on the self-renewal and senescence of hHFMSCs were investigated. Next-generation sequencing (NGS) was performed to identify the downstream genes of OCT4 in this process. Methylation-specific PCR (MSP) analysis was performed to measure the methylation level of the p21 promoter region. p21 was overexpressed in hHFMSCsOCT4 to test its downstream effect on OCT4. The regulatory effect of OCT4 on DNMTs was examined by ChIP assay. 5-aza-dC/zebularine was used to inhibit the expression of DNMTs, and then self-renewal properties and senescence in hHFMSCs were detected. RESULTS: The overexpression of OCT4 promoted proliferation, cell cycle progression, and osteogenic differentiation capacity of hHFMSCs. The cell senescence of hHFMSCs was markedly suppressed due to the ectopic expression of OCT4. Through NGS, we identified 2466 differentially expressed genes (DEGs) between hHFMSCsOCT4 and hHFMSCsEGFP, including p21, which was downregulated. The overexpression of p21 abrogated the proliferation and osteogenic differentiation capacity of hHFMSCsOCT4 and promoted cell senescence. OCT4 enhanced the transcription of DNMT genes, leading to an elevation in the methylation of the p21 promoter. The inhibition of DNMTs reversed the OCT4-induced p21 reduction, depleted the self-renewal of hHFMSCsOCT4, and triggered cell senescence. CONCLUSIONS: OCT4 maintains the self-renewal ability of hHFMSCs and reverses senescence by suppressing the expression of p21 through the upregulation of DNMTs. SN - 1757-6512 UR - https://www.unboundmedicine.com/medline/citation/30646941/OCT4_maintains_self_renewal_and_reverses_senescence_in_human_hair_follicle_mesenchymal_stem_cells_through_the_downregulation_of_p21_by_DNA_methyltransferases_ L2 - https://stemcellres.biomedcentral.com/articles/10.1186/s13287-018-1120-x DB - PRIME DP - Unbound Medicine ER -