scholarly journals Nsd2 Represses Endogenous Retrovirus MERVL in Embryonic Stem Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Tingting Gao ◽  
Fuquan Chen ◽  
Wenying Zhang ◽  
Xuan Zhao ◽  
Xiao Hu ◽  
...  
Keyword(s):  
Marker Gene ◽  
Embryonic Stem ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Body Region ◽  
Histone H2a ◽  
Transcription Start ◽  
Chimeric Transcripts ◽  
Gene Body Region ◽  
Pluripotency Genes

The facilitates chromatin transcription (FACT) complex is a histone H2A/H2B chaperone, which represses endogenous retroviruses (ERVs) and transcription of ERV-chimeric transcripts. It binds to both transcription start site and gene body region. Here, we investigated the downstream targets of FACT complex to identify the potential regulators of MERVL, which is a key 2-cell marker gene. H3K36me2 profile was positively correlated with that of FACT component Ssrp1. Among H3K36me2 deposition enzymes, Nsd2 was downregulated after the loss of Ssrp1. Furthermore, we demonstrated that Nsd2 repressed the expression of ERVs without affecting the expression of pluripotency genes. The expression of MERVL and 2-cell genes was partially rescued by Nsd2 overexpression. The enrichment of H3K36me2 decreased on MERVL-chimeric gene in ESCs without Ssrp1. Our study discovers that Nsd2 is a repressor of MERVL, and FACT partially represses MERVL expression by regulating the expression of Nsd2 and its downstream H3K36me2.

scholarly journals Zscan4c activates endogenous retrovirus MERVL and cleavage embryo genes

2019 ◽  
Author(s):  
Weiyu Zhang ◽  
Fuquan Chen ◽  
Ruiqing Chen ◽  
Dan Xie ◽  
Jiao Yang ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Embryonic Stem ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Enhancer Activity ◽  
Cell Cleavage ◽  
Cell Embryo ◽  
And Function ◽  
Scan Domain

AbstractEndogenous retroviruses (ERVs) contribute to ∼10 percent of the mouse genome. They are often silenced in differentiated somatic cells but differentially expressed at various embryonic developmental stages. A minority of mouse embryonic stem cells (ESCs), like 2-cell cleavage embryos, highly express ERV MERVL. However, the role of ERVs and mechanism of their activation in these cells are still poorly understood. In this study, we investigated the regulation and function of the stage-specific expressed ERVs, with a particular focus on the totipotency marker MT2/MERVL. We show that the transcription factor Zscan4c functions as an activator of MT2/MERVL and 2-cell/4-cell embryo genes. Zinc finger domains of Zscan4c play an important role in this process. In addition, Zscan4c interacts with MT2 and regulates MT2-nearby 2-cell/4-cell genes through promoting enhancer activity of MT2. Furthermore, MT2 activation is accompanied by enhanced H3K4me1, H3K27ac, and H3K14ac deposition on MT2. Zscan4c also interacts with GBAF chromatin remodelling complex through SCAN domain to further activate MT2 enhancer activity. Taken together, we delineate a previously unrecognized regulatory axis that Zscan4c interacts with and activates MT2/MERVL loci and their nearby genes through epigenetic regulation.

scholarly journals Fine Tuning of Histone Demethylase KDM6A/B Improves the Development of Nuclear Transfer Embryo

2018 ◽  
Author(s):  
Lei Yang ◽  
Lishuang Song ◽  
Xuefei Liu ◽  
Lige Bai ◽  
Guangpeng Li
Keyword(s):  
Nuclear Transfer ◽  
Embryonic Stem ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Fine Tuning ◽  
Mouse Strains ◽  
Low Efficiency ◽  
Nuclear Transfer Embryo ◽  
Genome Activation ◽  
Insight Into

AbstractDespite the success of the production of animals by somatic cell nuclear transfer (SCNT) in many species, the method is limited by a low efficiency. After zygotic genome activation (ZGA), a large number of endogenous retroviruses (ERVs) are expressed, including the murine endogenous retrovirus-L (MuERVL/MERVL). In this study, we generated a series of MERVL-reporter mouse strains to detect the ZGA event in embryos. We found that the majority of SCNT embryos exhibited ZGA failure, and histone H3 lysine 27 trimethylation (H3K27me3) prevented SCNT reprogramming. Overexpression of the H3K27me3-specific demethylase KDM6A, but not KDM6B, improved the efficiency of SCNT. Conversely, knockdown KDM6B not only facilitate ZGA, but also impede ectopic Xist expression in SCNT reprogramming. Furthermore, the knockdown of KDM6B increased the rate of SCNT-derived Duchenne muscular dystrophy embryonic stem cell establishment, indicate that these results not only provide insight into the mechanisms underlying failures of SCNT, but also may extend the applications of SCNT.

scholarly journals Stella modulates transcriptional and endogenous retrovirus programs during maternal-to-zygotic transition

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yun Huang ◽  
Jong Kyoung Kim ◽  
Dang Vinh Do ◽  
Caroline Lee ◽  
Christopher A Penfold ◽  
...  
Keyword(s):  
Developmental Process ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Cell Stage ◽  
Developmental Potential ◽  
Chimeric Transcripts ◽  
Embryonic Genome ◽  
Maternal To Zygotic Transition ◽  
Cell Embryo

The maternal-to-zygotic transition (MZT) marks the period when the embryonic genome is activated and acquires control of development. Maternally inherited factors play a key role in this critical developmental process, which occurs at the 2-cell stage in mice. We investigated the function of the maternally inherited factor Stella (encoded by Dppa3) using single-cell/embryo approaches. We show that loss of maternal Stella results in widespread transcriptional mis-regulation and a partial failure of MZT. Strikingly, activation of endogenous retroviruses (ERVs) is significantly impaired in Stella maternal/zygotic knockout embryos, which in turn leads to a failure to upregulate chimeric transcripts. Amongst ERVs, MuERV-L activation is particularly affected by the absence of Stella, and direct in vivo knockdown of MuERV-L impacts the developmental potential of the embryo. We propose that Stella is involved in ensuring activation of ERVs, which themselves play a potentially key role during early development, either directly or through influencing embryonic gene expression.

scholarly journals Human Endogenous Retrovirus Reactivation: Implications for Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1999
Author(s):  
Annacarmen Petrizzo ◽  
Concetta Ragone ◽  
Beatrice Cavalluzzo ◽  
Angela Mauriello ◽  
Carmen Manolio ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Genetic Material ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Danger Signal ◽  
Human Endogenous Retroviruses ◽  
Double Stranded Rna ◽  
Specific Antigens ◽  
Viral Mimicry

Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can be induced either by drugs or by cellular changes occurring in tumor cells. Indeed, several studies indicate that HERV proviral DNA can be transcribed either to double-stranded RNA (dsRNA) that is sensed as a “danger signal” by pattern recognition receptors (PRRs), leading to a viral mimicry state, or to mRNA that is translated into proteins that may contribute to the landscape of tumor-specific antigens (TSAs). Alternatively, HERV reactivation is associated with the expression of long noncoding RNAs (lncRNAs). In this review, we will highlight recent findings on HERV reactivation in cancer and its implications for cancer immunotherapy.

scholarly journals Identification and Characterization of Novel Human Endogenous Retrovirus Families by Phylogenetic Screening of the Human Genome Mapping Project Database

2000 ◽  
Vol 74 (8) ◽  
pp. 3715-3730 ◽  
Author(s):  
Michael Tristem
Keyword(s):  
Human Genome ◽  
Genome Mapping ◽  
Sequence Data ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Sequence Information ◽  
Class Iii ◽  
Genome Mapping Project ◽  
Human Genome Mapping Project

ABSTRACT Human endogenous retroviruses (HERVs) were first identified almost 20 years ago, and since then numerous families have been described. It has, however, been difficult to obtain a good estimate of both the total number of independently derived families and their relationship to each other as well as to other members of the familyRetroviridae. In this study, I used sequence data derived from over 150 novel HERVs, obtained from the Human Genome Mapping Project database, and a variety of recently identified nonhuman retroviruses to classify the HERVs into 22 independently acquired families. Of these, 17 families were loosely assigned to the class I HERVs, 3 to the class II HERVs and 2 to the class III HERVs. Many of these families have been identified previously, but six are described here for the first time and another four, for which only partial sequence information was previously available, were further characterized. Members of each of the 10 families are defective, and calculation of their integration dates suggested that most of them are likely to have been present within the human lineage since it diverged from the Old World monkeys more than 25 million years ago.

scholarly journals Infection of Nonhuman Primate Cells by Pig Endogenous Retrovirus

2000 ◽  
Vol 74 (16) ◽  
pp. 7687-7690 ◽  
Author(s):  
Juergen H. Blusch ◽  
Clive Patience ◽  
Yasuhiro Takeuchi ◽  
Christian Templin ◽  
Christian Roos ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Cell Lines ◽  
Nonhuman Primate ◽  
Endogenous Retrovirus ◽  
Papio Hamadryas ◽  
Endogenous Retroviruses ◽  
Human Donor ◽  
Baboon Model ◽  
Primate Cell ◽  
Perv Transmission

ABSTRACT The ongoing shortage of human donor organs for transplantation has catalyzed new interest in the application of pig organs (xenotransplantation). One of the biggest concerns about the transplantation of porcine grafts into humans is the transmission of pig endogenous retroviruses (PERV) to the recipients or even to other members of the community. Although nonhuman primate models are excellently suited to mimic clinical xenotransplantation settings, their value for risk assessment of PERV transmission at xenotransplantation is questionable since all of the primate cell lines tested so far have been found to be nonpermissive for PERV infection. Here we demonstrate that human, gorilla, and Papio hamadryas primary skin fibroblasts and also baboon B-cell lines are permissive for PERV infection. This suggests that a reevaluation of the suitability of the baboon model for risk assessment in xenotransplantation is critical at this point.

scholarly journals HERV-K HML-2 transcription in diverse cancers is related with cancer stem cell and epithelial-mesenchymal transition markers

2018 ◽  
Author(s):  
Audrey T. Lin ◽  
Cindy G. Santander ◽  
Fabricia F. Nascimento ◽  
Emanuele Marchi ◽  
Timokratis Karamitros ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Human Genome ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Mesenchymal Transition

AbstractEndogenous retroviruses (ERVs) are remnants of ancient retroviral infections that make up 8% of the human genome. Although these elements are mostly fragmented and inactive, many proviruses belonging to the HERV-K (HML-2) family, the youngest lineage in the human genome, have intact open reading frames, some encoding for accessory genes called np9 and rec that interact with oncogenic pathways. Many studies have established that ERVs are transiently expressed in both stem cells and cancer, resulting in aberrant self-renewal and uncontrolled proliferation. np9 and rec expression are significantly correlated with a range of cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) biomarkers, including cellular receptors, transcription factors, and histone modifiers. Surprisingly, these ERV genes are negatively correlated with genes known to promote pluripotency in embryonic stem cell lines, such as Oct4. These results indicate that HERV-K (HML-2) is part of the transcriptional landscape responsible for cancer cells undergoing the phenotypic switch that characterises EMT. The discovery of np9 and rec’s correlation with CSC and EMT biomarkers suggest a yet undescribed role affecting the transitional CSC-like state in EMT and the shift towards cancer malignancy.ImportanceIn this study, we find that human endogenous retrovirus HERV-K (HML-2)-encoded genes np9 and rec are correlated with the expression of many biomarkers associated with cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT). There has been a significant effort to develop novel treatments targeting CSC and EMT-specific signalling pathways and cell surface markers. This research describes HERV-K (HML-2) as interacting or being part of the regulatory network that make up reversible cell state switching in EMT. Our findings suggest these specific HERVs may be good candidate biomarkers in identifying the transitional CSC-like states that are present during the progression of EMT and cancer metastasis.

scholarly journals The pluripotent stem cell-specific transcript ESRG is dispensable for human pluripotency

2020 ◽  
Author(s):  
Kazutoshi Takahashi ◽  
Michiko Nakamura ◽  
Megumi Narita ◽  
Akira Watanabe ◽  
Mai Ueda ◽  
...  
Keyword(s):  
Global Gene Expression ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Loss Of Function ◽  
Complete Excision ◽  
Differentiation Potential ◽  
Quantitative Expression ◽  
Differentiated Cells ◽  
Chimeric Transcripts ◽  
Non Coding Rnas

AbstractHuman pluripotent stem cells (PSCs) express human endogenous retrovirus type-H (HERV-H), which exists as more than a thousand copies on the human genome and frequently produces chimeric transcripts as long-non-coding RNAs (lncRNAs) fused with downstream neighbor genes. Previous studies showed that HERV-H expression is required for the maintenance of PSC identity, and aberrant HERV-H expression attenuates neural differentiation potentials, however, little is known about the actual of function of HERV-H. In this study, we focused on ESRG, which is known as a PSC-related HERV-H-driven lncRNA. The global transcriptome data of various tissues and cell lines and quantitative expression analysis of PSCs showed that ESRG expression is much higher than other HERV-Hs and tightly silenced after differentiation. However, the loss of function by the complete excision of the entire ESRG gene body using a CRISPR/Cas9 platform revealed that ESRG is dispensable for the maintenance of the primed and naïve pluripotent states. The loss of ESRG hardly affected the global gene expression of PSCs or the differentiation potential toward trilineage. Differentiated cells derived from ESRG-deficient PSCs retained the potential to be reprogrammed into induced PSCs (iPSCs) by the forced expression of OCT3/4, SOX2, and KLF4. In conclusion, ESRG is dispensable for the maintenance and recapturing of human pluripotency.

scholarly journals Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

2019 ◽  
Author(s):  
Özgen Deniz ◽  
Mamataz Ahmed ◽  
Christopher D. Todd ◽  
Ana Rio-Machin ◽  
Mark A. Dawson ◽  
...  
Keyword(s):  
Cell Lines ◽  
Leukemia Cell ◽  
Endogenous Retrovirus ◽  
Epigenetic Silencing ◽  
Endogenous Retroviruses ◽  
Transcriptional Networks ◽  
Hematopoietic Malignancy ◽  
Additional Layer ◽  
Leukemia Cell Lines ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a highly aggressive hematopoietic malignancy, defined by a series of genetic and epigenetic alterations, which result in deregulation of transcriptional networks. One understudied but important source of transcriptional regulators are transposable elements (TEs), which are widespread throughout the human genome. Aberrant usage of these sequences could therefore contribute to oncogenic transcriptional circuits. However, the regulatory influence of TEs and their links to disease pathogenesis remain unexplored in AML. Using epigenomic data from AML primary samples and leukemia cell lines, we identified six endogenous retrovirus (ERV) families with AML-associated enhancer chromatin signatures that are enriched in binding of key regulators of hematopoiesis and AML pathogenesis. Using both CRISPR-mediated locus-specific genetic editing and simultaneous epigenetic silencing of multiple ERVs, we demonstrate that ERV deregulation directly alters the expression of adjacent genes in AML. Strikingly, deletion or epigenetic silencing of an ERV-derived enhancer suppressed cell growth by inducing apoptosis in leukemia cell lines. Our work reveals that ERVs are a previously unappreciated source of AML enhancers that have the potential to play key roles in leukemogenesis. We suggest that ERV activation provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive tumour heterogeneity and evolution.

scholarly journals EGFR DNA Methylation Correlates With EGFR Expression, Immune Cell Infiltration, and Overall Survival in Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhanyu Xu ◽  
Fanglu Qin ◽  
Liqiang Yuan ◽  
Jiangbo Wei ◽  
Yu Sun ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Expression ◽  
Lung Adenocarcinoma ◽  
Methylation Level ◽  
Promoter Region ◽  
Body Region ◽  
Gene Body ◽  
Immune Infiltration ◽  
Cpg Sites ◽  
Gene Body Region

BackgroundThe epidermal growth factor receptor (EGFR) is a primary target of molecular targeted therapy for lung adenocarcinoma (LUAD). The mechanisms that lead to epigenetic abnormalities of EGFR in LUAD are still unclear. The purpose of our study was to evaluate the abnormal methylation of EGFR CpG sites as potential biomarkers for LUAD.MethodsTo assess the differentially methylation CpG sites of EGFR in LUAD, we used an integrative study of Illumina HumanMethylation450K and RNA-seq data from The Cancer Genome Atlas (TCGA). We evaluated and compared EGFR multiple-omics data to explore the role of CpG sites located in EGFR promoter regions and gene body regions and the association with transcripts, protein expression levels, mutations, and somatic copy number variation. We calculated the correlation coefficients between CpG sites of EGFR and immune infiltration fraction (by MCPcounter and ESTIMATE) and immune-related pathways in LUAD. Finally, we validated the differential methylation of clinically and prognostically relevant CpG sites using quantitative methylation-specific PCR (qMSP).ResultsWe found that the methylation level of many EGFR CpGs in the promoter region was negatively correlated with the transcription level, protein expression, and SCNV, while the methylation at the gene body region was positively correlated with these features. The methylation level of EGFR CpGs in the promoter region was positively correlated with the level of immune infiltration and IFN-γ signature, while the opposite was found for methylation of the gene body region. The qMSP results showed that cg02316066 had a high methylation level, while cg02166842 had a low methylation level in LUAD. There was a high degree of co-methylation between cg02316066 and cg03046247.ConclusionOur data indicate that EGFR is an epigenetic regulator in LUAD acting through DNA methylation. Our research provides a theoretical basis for the further detection of EGFR DNA methylation as a predictive biomarker for LUAD survival and immunotherapy.

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