The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity

Lu, Xinyi; Sachs, Friedrich; Ramsay, LeeAnn; Jacques, Pierre-Étienne; Göke, Jonathan; Bourque, Guillaume; Ng, Huck‐Hui

doi:10.1038/nsmb.2799

Cited by 379 publications

(398 citation statements)

References 26 publications

Supporting

Mentioning

370

Contrasting

Unclassified

Order By: Relevance

“…We generally observed a greater propensity for the expression of LTR-associated lncRNAs in ESCs over more differentiated cells, consistent with the work of others (Kelley and Rinn 2012). Indeed, expression of endogenous retroviral elements is common in mouse and human ESCs and was postulated to contribute to species-specific regulation of pluripotency and differentiation (Macfarlan et al 2012;Lu et al 2014). It will be interesting to investigate loss of additional LTR-associated lncRNAs with respect to their contribution to the ESC gene expression program.…”

Section: Discussionsupporting

confidence: 75%

Regulation of the ESC transcriptome by nuclear long noncoding RNAs

Bergmann

Eckersley-Maslin

et al. 2015

Genome Res.

View full text Add to dashboard Cite

Long noncoding (lnc)RNAs have recently emerged as key regulators of gene expression. Here, we performed high-depth poly(A)+ RNA sequencing across multiple clonal populations of mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs) to comprehensively identify differentially regulated lncRNAs. We establish a biologically robust profile of lncRNA expression in these two cell types and further confirm that the majority of these lncRNAs are enriched in the nucleus. Applying weighted gene coexpression network analysis, we define a group of lncRNAs that are tightly associated with the pluripotent state of ESCs. Among these, we show that acute depletion of Platr14 using antisense oligonucleotides impacts the differentiation- and development-associated gene expression program of ESCs. Furthermore, we demonstrate that Firre, a lncRNA highly enriched in the nucleoplasm and previously reported to mediate chromosomal contacts in ESCs, controls a network of genes related to RNA processing. Together, we provide a comprehensive, up-to-date, and high resolution compilation of lncRNA expression in ESCs and NPCs and show that nuclear lncRNAs are tightly integrated into the regulation of ESC gene expression.

show abstract

Section: Discussionsupporting

confidence: 75%

Regulation of the ESC transcriptome by nuclear long noncoding RNAs

Bergmann

Eckersley-Maslin

et al. 2015

Genome Res.

View full text Add to dashboard Cite

show abstract

“…An appropriate activation of these LTRs was shown to be essential for iPS reprogramming (Lu et al 2014;Ohnuki et al 2014). Depleting LTRs in ES cells led to cell differentiation (Fort et al 2014;Lu et al 2014), whereas augmenting LTRs impaired cell differentiation (Ohnuki et al 2014). Concordantly, we found that HCCs can be stratified according to LTR expression level and that LTR-high HCCs are less well-differentiated than LTR-low ones, confirming that an excess of LTR activity impairs cell differentiation.…”

Section: Discussionsupporting

confidence: 60%

“…The mechanisms of regulation of the LTRs was previously investigated in iPS and ES cells, which express high levels of specific LTR families, namely, LTR7 and HERVH. An appropriate activation of these LTRs was shown to be essential for iPS reprogramming (Lu et al 2014;Ohnuki et al 2014). Depleting LTRs in ES cells led to cell differentiation (Fort et al 2014;Lu et al 2014), whereas augmenting LTRs impaired cell differentiation (Ohnuki et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Other studies demonstrated a high activity of distinct LTR subfamilies in stem cells using several different methods, including RNA-seq (Kelley and Rinn 2012;St Laurent et al 2013), DNase-seq (Jacques et al 2013), and MeDIP-seq (Xie et al 2013). Furthermore, an appropriate activation of LTRs is essential for iPS reprogramming (Lu et al 2014;Ohnuki et al 2014), suggesting that the expression of LTRs might be associated with cancerous features, such as poor differentiation and high proliferation potency.…”

mentioning

confidence: 99%

See 1 more Smart Citation

CAGE profiling of ncRNAs in hepatocellular carcinoma reveals widespread activation of retroviral LTR promoters in virus-induced tumors

Hashimoto¹,

Suzuki²,

Santos

et al. 2015

Genome Res.

View full text Add to dashboard Cite

An increasing number of noncoding RNAs (ncRNAs) have been implicated in various human diseases including cancer; however, the ncRNA transcriptome of hepatocellular carcinoma (HCC) is largely unexplored. We used CAGE to map transcription start sites across various types of human and mouse HCCs with emphasis on ncRNAs distant from protein-coding genes. Here, we report that retroviral LTR promoters, expressed in healthy tissues such as testis and placenta but not liver, are widely activated in liver tumors. Despite HCC heterogeneity, a subset of LTR-derived ncRNAs were more than 10-fold up-regulated in the vast majority of samples. HCCs with a high LTR activity mostly had a viral etiology, were less differentiated, and showed higher risk of recurrence. ChIP-seq data show that MYC and MAX are associated with ncRNA deregulation. Globally, CAGE enabled us to build a mammalian promoter map for HCC, which uncovers a new layer of complexity in HCC genomics.

show abstract

“…Recent study by Lu et al showed that HERV-H activity regulated by OCT3/4 and p300 is important for generation and selfrenewal of iPSCs (20). Among OSKM reprogramming factors, we showed that KLF4 levels are the most important for activating and resuppressing LTR7s.…”

Section: Discussionmentioning

confidence: 78%

Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential

Ohnuki

Tanabe

Sutou

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

251

282

View full text Add to dashboard Cite

Significance In this study, we found that human endogenous retoriviruses type-H (HERV-Hs) are transiently hyperactivated during reprogramming toward induced pluripotent stem cells (iPSCs) and play important roles in this process. However, when reprogramming is complete and cells acquire full pluripotency, HERV-H activity should decrease to levels comparable with those in embryonic stem cells because failure to resilence this activity leads to the differentiation-defective phenotype in neural lineage. We also found that during reprogramming, reprogramming factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), and Krüppel-like factor 4 (KLF4) (OSK) bind to and activate long-terminal repeats of HERV-Hs. KLF4 possibly precludes Tripartite motif containing 28 and recruits not only OCT3/4 and SOX2, but also E1A binding protein p300 (p300) histone acethyltransferase on HERV-H loci. Therefore, OKSM-induced HERV-H activation constitutes an unanticipated and critical mechanism for iPSC formation.

show abstract

The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity

Cited by 379 publications

References 26 publications

Regulation of the ESC transcriptome by nuclear long noncoding RNAs

Regulation of the ESC transcriptome by nuclear long noncoding RNAs

CAGE profiling of ncRNAs in hepatocellular carcinoma reveals widespread activation of retroviral LTR promoters in virus-induced tumors

Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential

Contact Info

Product

Resources

About