Abstract
Pluripotent stem cells (PSCs) have the potential to produce any types of cells from all three basic germ layers and the capacity to self-renew and proliferate indefinitely in vitro. The two main types of PSCs, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), share common features such as colony morphology, high expression of Oct4 and Nanog, and strong alkaline phosphatase activity. In recent years, increasing evidences suggest that telomere length represents another important internal factor in maintaining stem cell pluripotency. Telomere length homeostasis and its structural integrity help to protect chromosome ends from recombination, end fusion, and DNA damage responses, ensuring the divisional ability of mammalian cells. PSCs generally exhibit high telomerase activity to maintain their extremely long and stable telomeres, and emerging data indicate the alternative lengthening of telomeres (ALT) pathway may play an important role in telomere functions too. Such characteristics are likely key to their abilities to differentiate into diverse cell types in vivo. In this review, we will focus on the function and regulation of telomeres in ESCs and iPSCs, thereby shedding light on the importance of telomere length to pluripotency and the mechanisms that regulate telomeres in PSCs.
Highlights
Telomeres are hexametric repeats of (TTAGGG)n at the chromosomal ends in mammalian cells
The telomere region is bound by a six-protein complex called shelterin/telosome, containing TRF1, TRF2, TPP1, POT1, TIN2 and RAP1, which is crucial for maintaining the structure and function of telomeres
alternative lengthening of telomeres (ALT) has been found to occur in about 10%–15% cancers and is often characterized by co-localization of telomeres with the promyelocytic leukemia (PML) bodies (known as ALT-associated PML bodies (APBs)), exceedingly heterogeneous telomere length, extra-chromosomal DNA circles, and high frequencies of telomere sister chromatid exchange (T-SCE) (Cesare and Reddel, 2010; Chung et al, 2012)
Summary
Pluripotent stem cells, including the well-studied ESCs and emerging iPSCs, promise great potential applications in the medical and drug field. Many transcription factors that control cell fate determination are epigenetically marked by either active (such as methylated H3K4) or repressive (like methylated H3K27) histone modifications These bivalent chromatin states provide the plasticity for maintaining ESC pluripotency and regulating the expression level of lineage-specific genes during differentiation (Bernstein et al, 2006). For iPSCs, the epigenetic status of successfully induced cells is highly similar to the ESCs, including changes in histone modifications and DNA methylation at the gene loci that are required for the maintenance of pluripotency and lineage specification, as well as efficient activation of the telomerase and elongation of telomeres (Marion et al, 2009; Takahashi et al, 2007; Takahashi and Yamanaka, 2006). The telomeres in PSCs, which can be regulated in a telomerase-dependent or independent (e.g. ALT) fashion, are crucial for PSC biology, which will be discussed
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