Trends in Genetics
ReviewLinking Telomere Regulation to Stem Cell Pluripotency
Section snippets
Pluripotent Stem Cells
PSCs (see Glossary) including ESCs, somatic cell nuclear transfer ESCs (scntESCs), and iPSCs have a unique competence for unlimited self-renewal and pluripotency. Unlimited self-renewal is essential for expanding cell cultures to achieve a large number of cells sufficient for clinical applications in stem cell-based therapy. The pluripotency characteristic is equally important in that these cells have the capacity to differentiate into all cell types that comprise an individual. Therefore, they
Role of Telomerase in Telomere Maintenance
Telomerase is activated in stem cells and germ cells during human embryonic development and differentiation, and in cancers. Telomerase also is strongly expressed and required for telomere maintenance and the long-term self-renewal and pluripotency of mouse and human PSCs (Box 2) 9, 10, 11, 12, 13, 14, 15. Moreover, mRtel1 is required for DNA replication, recombination, and repair, and for the efficient elongation of telomeres by telomerase in mESCs 16, 17. Mouse ESCs (mESCs) and/or iPSCs with
Epigenetic Regulation of Telomere Length Maintenance and Homeostasis
Compared with differentiated somatic cells, the heterochromatic telomeric chromatin of ESCs is in a less compact state with relatively lower levels of H3K9me3 and H4K20me3 21, 47. Original findings suggest that DNA methylation negatively regulates telomere lengths [48]. mESCs deficient for the DNA methyltransferases DNMT1, or both DNMT3a and DNMT3b, exhibit dramatically elongated telomeres compared with wildtype controls, associated with increased telomeric recombination, as indicated by TSCE
Remarkable Telomere Elongation in miPSCs
Telomere shortening leads to cell senescence and organism aging. Reprogramming of telomerase and telomeres during induction of iPSCs occurs gradually, but before activation of endogenous pluripotent genes [22]. Telomeres continue to elongate during passages with acquisition of full reprogramming to pluripotency.
Pluripotency transcription factors can activate telomerase genes. The Terc promoter is bound and activated by OCT3/4 and NANOG [108]. Tert upregulation occurs simultaneously with the
Telomere Reprogramming Links to Somatic Cell Reprogramming and Pluripotency
Somatic cell nuclear transfer (SCNT) using oocytes was exploited to generate nuclear transfer embryos from which pluripotent scntESCs are then derived. If we can discover the secrets of how eggs can efficiently reprogram somatic cell nuclei by nuclear transfer, some of these egg molecules or mechanisms could be incorporated into the iPS route to improve the efficiency and cell number production of therapeutically useful cells [119]. Nuclear transfer allows somatic cells to undergo extensive
Insights Into Telomere Reprogramming by SCNT for Improving iPSC Induction and Quality
iPSC quality can be improved using reprogramming factors in early embryos. Zscan4 addition into Yamanaka factors enhances telomere reprogramming and the elongation and genomic stability of miPSCs [139]. Consistently, small molecules that activate Zscan4 expression increase the generation of high quality iPSCs with preservation of genomic integrity [140]. Coincidently, these molecules (e.g., SB431542, PD0325901, and AZA) reportedly enhance somatic cell reprogramming and iPSC induction and
Concluding Remarks
Sufficient telomere lengths and genomic stability are critical for the unlimited self-renewal and pluripotency of PSCs. Telomere lengths and homeostasis in ESCs and/or iPSCs are regulated by epigenetic modifications and their modulators, in addition to telomerase activity. Histone acetylation, and the Tbx3 and Tet enzymes act as positive regulators and Rif1, BRCA1, H3.3/ATRX/DAXX/DEK, CAF-1, and Nr0b1 act as negative regulators of telomere length via epigenetic modifications. Moreover, ESC
Acknowledgments
I am grateful to all of my laboratory members, past and present, and to my collaborators and colleagues in the field for helping with the critical experiments and fruitful discussion that led to this review. I apologize for being unable to explicitly discuss other important contributions due to space limitations and my knowledge. I also would like to thank the funding from the China Ministry of Science and Technology Major Research Program, Program of International S&T Cooperation, and the
Glossary
- Chimera production test
- an in vivo assay of developmental pluripotency of PSCs by injection of the cells into recipient blastocysts, or into or aggregation with early cleavage embryos from different origins to create chimeras by combining embryos of two or more genotypes, demonstrating the competence of PSCs to contribute to all cell lineages of a mouse, including the germ line.
- Embryonic stem cells (ESCs)
- these classical PSCs are isolated from early cleavage embryos or the inner cell mass (ICM)
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2021, Translational OncologyCitation Excerpt :Telomere length maintenance is critical for the unlimited self-renewal and pluripotency of a stem cell. Pluripotent stem cells need to preserve their telomere length and homeostasis to maintain their self-renewal ability and pluripotency [51–53]. We found that ALDH+CD44+CXCR4+CD24+ cells exhibited shorter-length telomeres after TAP1 treatment.
Tet2 regulates Barx2 expression in undifferentiated and early differentiated mouse embryonic stem cells
2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :TET family proteins also regulate pluripotency by controlling telomere length that stabilizes the genomic and maintains self-renewal and pluripotency. TET2 knockdown cells exhibit downregulated telomere recombination genes [34,35]. And Tet2 primes the regulatory regions of the genome to activate mESC differentiation [15,26].
Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness
2020, Journal of Biological ChemistryCitation Excerpt :Induced pluripotent stem cells (iPSCs) have rapidly gained significance in basic and applied biological sciences (84) and serve as a facile model system for cellular differentiation and development. The important role of telomere elongation and homeostasis in formation/maintenance of iPSCs, including their implications in aging, is known (25, 85). In the following sections, we discuss the importance of telomeres in self-renewal and chromosome stability in iPSCs and consider emerging literature on how extra-telomeric function of telomere-associated factors might influence pluripotency.
High homocysteine promotes telomere dysfunction and chromosomal instability in human neuroblastoma SH-SY5Y cells
2020, Mutation Research - Genetic Toxicology and Environmental MutagenesisCitation Excerpt :When TL becomes critically short, it may induce chromosomal instability (CIN), growth arrest, or cell death, and contribute to tissue damage and aging [1,3]. Thus, the efficient maintenance of TL is important for cells with unlimited self-renewal and proliferation capacity, such as stem cells and cancer cells [3,4]. In these cells, TL homeostasis is carried out primarily by telomerase, a reverse transcriptase, encoded by TERT.
The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients
2024, Nature Communications