Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells
Abstract Background Naïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. However, the molecular mechanisms und...
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doaj-cdf2d64be7ee423badea3c6995e429cf2021-07-11T11:50:31ZengBMCGenome Biology1474-760X2021-07-0122113010.1186/s13059-021-02417-9Elevated retrotransposon activity and genomic instability in primed pluripotent stem cellsHaifeng Fu0Weiyu Zhang1Niannian Li2Jiao Yang3Xiaoying Ye4Chenglei Tian5Xinyi Lu6Lin Liu7State Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, Nankai UniversityAbstract Background Naïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. However, the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive. Results We examine the regulation of telomere maintenance, retrotransposon activity, and genomic stability of primed PSCs and compare them with naïve PSCs. Surprisingly, primed PSCs only minimally maintain telomeres and show fragile telomeres, associated with declined DNA recombination and repair activity, in contrast to naïve PSCs that robustly elongate telomeres. Also, we identify LINE1 family integrant L1Md_T as naïve-specific retrotransposon and ERVK family integrant IAPEz to define primed PSCs, and their transcription is differentially regulated by heterochromatic histones and Dnmt3b. Notably, genomic instability of primed PSCs is increased, in association with aberrant retrotransposon activity. Conclusions Our data suggest that fragile telomere, retrotransposon-associated genomic instability, and declined DNA recombination repair, together with reduced function of cell cycle and mitochondria, increased apoptosis, and differentiation properties may link to compromised developmental potency of primed PSCs, noticeably distinguishable from naïve PSCs.https://doi.org/10.1186/s13059-021-02417-9Naïve and primed pluripotent stateTelomeres2C genesGenome stabilityRetrotransposonsHistone modifications |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Haifeng Fu Weiyu Zhang Niannian Li Jiao Yang Xiaoying Ye Chenglei Tian Xinyi Lu Lin Liu |
spellingShingle |
Haifeng Fu Weiyu Zhang Niannian Li Jiao Yang Xiaoying Ye Chenglei Tian Xinyi Lu Lin Liu Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells Genome Biology Naïve and primed pluripotent state Telomeres 2C genes Genome stability Retrotransposons Histone modifications |
author_facet |
Haifeng Fu Weiyu Zhang Niannian Li Jiao Yang Xiaoying Ye Chenglei Tian Xinyi Lu Lin Liu |
author_sort |
Haifeng Fu |
title |
Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells |
title_short |
Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells |
title_full |
Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells |
title_fullStr |
Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells |
title_full_unstemmed |
Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells |
title_sort |
elevated retrotransposon activity and genomic instability in primed pluripotent stem cells |
publisher |
BMC |
series |
Genome Biology |
issn |
1474-760X |
publishDate |
2021-07-01 |
description |
Abstract Background Naïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. However, the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive. Results We examine the regulation of telomere maintenance, retrotransposon activity, and genomic stability of primed PSCs and compare them with naïve PSCs. Surprisingly, primed PSCs only minimally maintain telomeres and show fragile telomeres, associated with declined DNA recombination and repair activity, in contrast to naïve PSCs that robustly elongate telomeres. Also, we identify LINE1 family integrant L1Md_T as naïve-specific retrotransposon and ERVK family integrant IAPEz to define primed PSCs, and their transcription is differentially regulated by heterochromatic histones and Dnmt3b. Notably, genomic instability of primed PSCs is increased, in association with aberrant retrotransposon activity. Conclusions Our data suggest that fragile telomere, retrotransposon-associated genomic instability, and declined DNA recombination repair, together with reduced function of cell cycle and mitochondria, increased apoptosis, and differentiation properties may link to compromised developmental potency of primed PSCs, noticeably distinguishable from naïve PSCs. |
topic |
Naïve and primed pluripotent state Telomeres 2C genes Genome stability Retrotransposons Histone modifications |
url |
https://doi.org/10.1186/s13059-021-02417-9 |
work_keys_str_mv |
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