Critically short telomeres derepress retrotransposons to promote genome instability in embryonic stem cells

Abstract

Telomeres, at the ends of chromosomes, protect chromosomes from fusion and preserve genomic stability. However, the molecular mechanisms underlying telomere attrition-induced genome instability remain to be understood. We systematically analyzed the expression of retrotransposons and performed genomic sequencing of different cell and tissue types with telomeres of varying lengths due to telomerase deficiency. We found that critically short telomeres altered retrotransposon activity to promote genomic instability in mouse embryonic stem cells, as evidenced by elevated numbers of single nucleotide variants, indels and copy number variations (CNVs). Transpositions of retrotransposons such as LINE1 resulting from the short telomeres can also be found in these genomes with elevated number of mutations and CNVs. Retrotransposon activation is linked to increased chromatin accessibility, and reduced heterochromatin abundance correlates with short telomeres. Re-elongation of telomeres upon recovery of telomerase partly represses retrotransposons and heterochromatin accumulation. Together, our findings suggest a potential mechanism by which telomeres maintain genomic stability by suppressing chromatin accessibility and retrotransposon activity.

A rapid and stable spontaneous reprogramming system of Spermatogonial stem cells to Pluripotent State

“…Using these transcriptome data, we further compared the gene expression profiles of GSPCs and ES-like cells with ESCs, the well characterized pluripotent cells. We obtained RNA-seq datasets of wild-type mouse embryonic stem cells from the Gene Expression Omnibus (GEO) database [ 19 ] and performed a comparative analysis with our study’s dataset. After eliminating batch effects among the data, principal component analysis (PCA) was conducted on individual samples (Figure S5 a).…”

“…The wild-type mouse ESCs dataset originated from the following studies: GSM5589123, GSM5589124 [ 19 ]. Raw data for ESCs were obtained and jointly analyzed with raw data for ES-like cells, GSPCs, and SSCs.…”

Regulation of endogenous retroviruses in murine embryonic stem cells and early embryos

“…Mouse ESCs are characterized by their long telomeres, which are maintained by telomerase and other telomere-associated factors ( Liu, 2017 ). Telomere shortening can activate the expression of ERVs, including MERVL, IAPEy, and ERVB3/4 ( Zhao et al., 2023a ). The MERVL-activating transcription factor Zscan4 is one of the factors that promote telomere lengthening through alternative extension of telomeres ( Zalzman et al., 2010 ).…”