Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells

Fu, Haifeng; Zhang, Weiyu; Li, Niannian; Yang, Jiao; Ye, Xiaoying; Tian, Chenglei; Lu, Xinyi; Liu, Lin

doi:10.1186/s13059-021-02417-9

Cited by 14 publications

(5 citation statements)

References 107 publications

(168 reference statements)

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“…IAPEz are young, mouse-specific ERVKs. ChIP-seq data for mUHRF1 and the histone H3 marks from mESC were published previously [ 54 , 60 , 61 ] …”

Section: Resultsmentioning

confidence: 99%

RepEnTools: an automated repeat enrichment analysis package for ChIP-seq data reveals hUHRF1 Tandem-Tudor domain enrichment in young repeats

Choudalakis,

Bashtrykov,

Jeltsch

2024

Mobile DNA

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Background Repeat elements (REs) play important roles for cell function in health and disease. However, RE enrichment analysis in short-read high-throughput sequencing (HTS) data, such as ChIP-seq, is a challenging task. Results Here, we present RepEnTools, a software package for genome-wide RE enrichment analysis of ChIP-seq and similar chromatin pulldown experiments. Our analysis package bundles together various software with carefully chosen and validated settings to provide a complete solution for RE analysis, starting from raw input files to tabular and graphical outputs. RepEnTools implementations are easily accessible even with minimal IT skills (Galaxy/UNIX). To demonstrate the performance of RepEnTools, we analysed chromatin pulldown data by the human UHRF1 TTD protein domain and discovered enrichment of TTD binding on young primate and hominid specific polymorphic repeats (SVA, L1PA1/L1HS) overlapping known enhancers and decorated with H3K4me1-K9me2/3 modifications. We corroborated these new bioinformatic findings with experimental data by qPCR assays using newly developed primate and hominid specific qPCR assays which complement similar research tools. Finally, we analysed mouse UHRF1 ChIP-seq data with RepEnTools and showed that the endogenous mUHRF1 protein colocalizes with H3K4me1-H3K9me3 on promoters of REs which were silenced by UHRF1. These new data suggest a functional role for UHRF1 in silencing of REs that is mediated by TTD binding to the H3K4me1-K9me3 double mark and conserved in two mammalian species. Conclusions RepEnTools improves the previously available programmes for RE enrichment analysis in chromatin pulldown studies by leveraging new tools, enhancing accessibility and adding some key functions. RepEnTools can analyse RE enrichment rapidly, efficiently, and accurately, providing the community with an up-to-date, reliable and accessible tool for this important type of analysis.

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“…IAPEz are young, mouse-specific ERVKs. ChIP-seq data for mUHRF1 and the histone H3 marks from mESC were published previously [ 54 , 60 , 61 ] …”

Section: Resultsmentioning

confidence: 99%

RepEnTools: an automated repeat enrichment analysis package for ChIP-seq data reveals hUHRF1 Tandem-Tudor domain enrichment in young repeats

Choudalakis,

Bashtrykov,

Jeltsch

2024

Mobile DNA

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“…Importantly, de-repression of transposons has been found in a wide range of diseases and is potentially responsible for the underlying chronic inflammatory phenotype [36,[52][53][54]. TE expression and dsRNA also occur in pluripotent stem cells [55] and during hematopoietic development, though in the immune-privileged environment, other protective mechanisms appear to play a role, such as RNA methylation (m6A) [56].…”

Section: Discussionmentioning

confidence: 99%

Significant Variations in Double-Stranded RNA Levels in Cultured Skin Cells

Sadeq,

Chitcharoen,

Al-Hashimi

et al. 2024

Cells

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Endogenous double-stranded RNA has emerged as a potent stimulator of innate immunity. Under physiological conditions, endogenous dsRNA is maintained in the cell nucleus or the mitochondria; however, if protective mechanisms are breached, it leaches into the cytoplasm and triggers immune signaling pathways. Ectopic activation of innate immune pathways is associated with various diseases and senescence and can trigger apoptosis. Hereby, the level of cytoplasmic dsRNA is crucial. We have enriched dsRNA from two melanoma cell lines and primary dermal fibroblasts, including a competing probe, and analyzed the dsRNA transcriptome using RNA sequencing. There was a striking difference in read counts between the cell lines and the primary cells, and the effect was confirmed by northern blotting and immunocytochemistry. Both mitochondria (10–20%) and nuclear transcription (80–90%) contributed significantly to the dsRNA transcriptome. The mitochondrial contribution was lower in the cancer cells compared to fibroblasts. The expression of different transposable element families was comparable, suggesting a general up-regulation of transposable element expression rather than stimulation of a specific sub-family. Sequencing of the input control revealed minor differences in dsRNA processing pathways with an upregulation of oligoadenylate synthase and RNP125 that negatively regulates the dsRNA sensors RIG1 and MDA5. Moreover, RT-qPCR, Western blotting, and immunocytochemistry confirmed the relatively minor adaptations to the hugely different dsRNA levels. As a consequence, these transformed cell lines are potentially less tolerant to interventions that increase the formation of endogenous dsRNA.

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“…Epigenetic activation of LINE1s and their retrotransposition were also found in various human diseases, related to genome instability 74 , 75 . Activation of LINE1 retrotransposition may further contribute to the alteration of gene expression, genome instability, mutations 76 – 78 and cancer development 72 . For example, the proto-oncogene Ret was activated after LINE1 retrotransposition into a nearby region (Figs.…”

Section: Discussionmentioning

confidence: 99%

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

Zhao

Yin

et al. 2023

Cell Discov

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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.

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Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells

Cited by 14 publications

References 107 publications

RepEnTools: an automated repeat enrichment analysis package for ChIP-seq data reveals hUHRF1 Tandem-Tudor domain enrichment in young repeats

RepEnTools: an automated repeat enrichment analysis package for ChIP-seq data reveals hUHRF1 Tandem-Tudor domain enrichment in young repeats

Significant Variations in Double-Stranded RNA Levels in Cultured Skin Cells

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

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