scholarly journals Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 783 ◽  
Author(s):  
Rita Rebollo ◽  
Mariana Galvão-Ferrarini ◽  
Liane Gagnier ◽  
Ying Zhang ◽  
Ardian Ferraj ◽  
...  
Keyword(s):  
Es Cells ◽  
Inbred Mice ◽  
Embryonic Stem ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
C3h Mice ◽  
In Trans ◽  
Epigenetic Repression ◽  
Intracisternal A Particle ◽  
Reading Frames

Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate the mechanism for high IAP activity in C3H mice, we identified 61 IAP copies in C3H/HeJ ES cells enriched with H3K4me3 (a mark of active promoters) and, among those tested, all are unmethylated in C3H/HeJ ES cells. Notably, 13 of the 61 are specific to C3H/HeJ and are members of the non-autonomous 1Δ1 IAP subfamily that is responsible for nearly all new insertions in C3H. One copy is full length with intact open reading frames and hence potentially capable of providing proteins in trans to other 1Δ1 elements. This potential “master copy” is present in other strains, including 129, but its 5’ long terminal repeat (LTR) is methylated in 129 ES cells. Thus, the unusual IAP activity in C3H may be due to reduced epigenetic repression coupled with the presence of a master copy.

scholarly journals DNA polymerase α interacts with H3-H4 and facilitates the transfer of parental histones to lagging strands

2020 ◽  
Vol 6 (35) ◽  
pp. eabb5820 ◽  
Author(s):  
Zhiming Li ◽  
Xu Hua ◽  
Albert Serra-Cardona ◽  
Xiaowei Xu ◽  
Songlin Gan ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Es Cells ◽  
Embryonic Stem ◽  
Endogenous Retroviruses ◽  
Histone Binding ◽  
Dna Polymerase Α ◽  
Mouse Es Cells ◽  
Dna Strands ◽  
Histone Deposition

How parental histones, the carriers of epigenetic modifications, are deposited onto replicating DNA remains poorly understood. Here, we describe the eSPAN method (enrichment and sequencing of protein-associated nascent DNA) in mouse embryonic stem (ES) cells and use it to detect histone deposition onto replicating DNA strands with a relatively small number of cells. We show that DNA polymerase α (Pol α), which synthesizes short primers for DNA synthesis, binds histone H3-H4 preferentially. A Pol α mutant defective in histone binding in vitro impairs the transfer of parental H3-H4 to lagging strands in both yeast and mouse ES cells. Last, dysregulation of both coding genes and noncoding endogenous retroviruses is detected in mutant ES cells defective in parental histone transfer. Together, we report an efficient eSPAN method for analysis of DNA replication–linked processes in mouse ES cells and reveal the mechanism of Pol α in parental histone transfer.

scholarly journals Characterization of Endogenous Retroviruses in Sheep

2003 ◽  
Vol 77 (20) ◽  
pp. 11268-11273 ◽  
Author(s):  
Nikolai Klymiuk ◽  
Mathias Müller ◽  
Gottfried Brem ◽  
Bernhard Aigner
Keyword(s):  
Endogenous Retrovirus ◽  
Ovis Aries ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
In Vivo Experiments ◽  
Pregnant Sheep ◽  
Reading Frames

ABSTRACT Endogenous retrovirus (ERV) sequences have been found in all mammals. In vitro and in vivo experiments revealed ERV activation and cross-species infection in several species. Sheep (Ovis aries) are used for various biotechnological purposes; however, they have not yet been comprehensively screened for ERV sequences. Therefore, the aim of the study was to classify the ERV sequences in the ovine genome (OERV) by analyzing the retroviral pro-pol sequences. Three OERV β families and nine OERV γ families were revealed. Novel open reading frames (ORF) in the amplified proviral fragment were found in one OERV β family and two OERV γ families. Hybrid OERV produced by putative recombination events were not detected. Quantitative analysis of the OERV sequences in the ovine genome revealed no relevant variations in the endogenous retroviral loads of different breeds. Expression analysis of different tissues from fetal and pregnant sheep detected mRNA from both gammaretrovirus families, showing ORF fragments. Thus, the release of retroviruses from sheep cells cannot be excluded.

scholarly journals Retroviral Transcriptional Regulation and Embryonic Stem Cells: War and Peace

2014 ◽  
Vol 35 (5) ◽  
pp. 770-777 ◽  
Author(s):  
Sharon Schlesinger ◽  
Stephen P. Goff
Keyword(s):  
Dna Sequences ◽  
Regulatory Networks ◽  
Es Cells ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Cell Types ◽  
Endogenous Retroviruses ◽  
Regulatory Sequences ◽  
Cellular Genes ◽  
Wide Range

Retroviruses have evolved complex transcriptional enhancers and promoters that allow their replication in a wide range of tissue and cell types. Embryonic stem (ES) cells, however, characteristically suppress transcription of proviruses formed after infection by exogenous retroviruses and also of most members of the vast array of endogenous retroviruses in the genome. These cells have unusual profiles of transcribed genes and are poised to make rapid changes in those profiles upon induction of differentiation. Many of the transcription factors in ES cells control both host and retroviral genes coordinately, such that retroviral expression patterns can serve as markers of ES cell pluripotency. This overlap is not coincidental; retrovirus-derived regulatory sequences are often used to control cellular genes important for pluripotency. These sequences specify the temporal control and perhaps “noisy” control of cellular genes that direct proper cell gene expression in primitive cells and their differentiating progeny. The evidence suggests that the viral elements have been domesticated for host needs, reflecting the wide-ranging exploitation of any and all available DNA sequences in assembling regulatory networks.

scholarly journals Ancient Adversary – HERV-K (HML-2) in Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Eoin Dervan ◽  
Dibyangana D. Bhattacharyya ◽  
Jake D. McAuliffe ◽  
Faizan H. Khan ◽  
Sharon A. Glynn
Keyword(s):  
Tumour Progression ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
Human Endogenous Retroviruses ◽  
Viral Particles ◽  
Metastatic Capacity ◽  
Coding Capacity ◽  
Reading Frames

Human endogenous retroviruses (HERV), ancient integrations of exogenous viruses, make up 8% of our genome. Long thought of as mere vestigial genetic elements, evidence is now accumulating to suggest a potential functional role in numerous pathologies including neurodegenerative diseases, autoimmune disorders, and multiple cancers. The youngest member of this group of transposable elements is HERV-K (HML-2). Like the majority of HERV sequences, significant post-insertional mutations have disarmed HERV-K (HML-2), preventing it from producing infectious viral particles. However, some insertions have retained limited coding capacity, and complete open reading frames for all its constituent proteins can be found throughout the genome. For this reason HERV-K (HML-2) has garnered more attention than its peers. The tight epigenetic control thought to suppress expression in healthy tissue is lost during carcinogenesis. Upregulation of HERV-K (HML-2) derived mRNA and protein has been reported in a variety of solid and liquid tumour types, and while causality has yet to be established, progressively more data are emerging to suggest this phenomenon may contribute to tumour growth and metastatic capacity. Herein we discuss its potential utility as a diagnostic tool and therapeutic target in light of the current in vitro, in vivo and clinical evidence linking HERV-K (HML-2) to tumour progression.

scholarly journals Molecular Characterization and Placental Expression of HERV-W, a New Human Endogenous Retrovirus Family

1999 ◽  
Vol 73 (2) ◽  
pp. 1175-1185 ◽  
Author(s):  
Jean-Luc Blond ◽  
Frédéric Besème ◽  
Laurent Duret ◽  
Olivier Bouton ◽  
Frédéric Bedin ◽  
...  
Keyword(s):  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
Primer Binding Site ◽  
Human Endogenous Retrovirus ◽  
Cdna Clones ◽  
Human Endogenous Retroviruses ◽  
Herv Family ◽  
Flanking Sequences ◽  
Reading Frames

ABSTRACT The multiple sclerosis-associated retrovirus (MSRV) isolated from plasma of MS patients was found to be phylogenetically and experimentally related to human endogenous retroviruses (HERVs). To characterize the MSRV-related HERV family and to test the hypothesis of a replication-competent HERV, we have investigated the expression of MSRV-related sequences in healthy tissues. The expression of MSRV-related transcripts restricted to the placenta led to the isolation of overlapping cDNA clones from a cDNA library. These cDNAs spanned a 7.6-kb region containing gag, pol, and env genes; RU5 and U3R flanking sequences; a polypurine tract; and a primer binding site (PBS). As this PBS showed similarity to avian retrovirus PBSs used by tRNATrp, this new HERV family was named HERV-W. Several genomic elements were identified, one of them containing a complete HERV-W unit, spanning all cDNA clones. Elements of this multicopy family were not replication competent, asgag and pol open reading frames (ORFs) were interrupted by frameshifts and stop codons. A complete ORF putatively coding for an envelope protein was found both on the HERV-W DNA prototype and within an RU5-env-U3R polyadenylated cDNA clone. Placental expression of 8-, 3.1-, and 1.3-kb transcripts was observed, and a putative splicing strategy was described. The apparently tissue-restricted HERV-W long terminal repeat expression is discussed with respect to physiological and pathological contexts.

scholarly journals Biological Functions of DNA Methyltransferase 1 Require Its Methyltransferase Activity

2007 ◽  
Vol 27 (11) ◽  
pp. 3891-3899 ◽  
Author(s):  
Marc Damelin ◽  
Timothy H. Bestor
Keyword(s):  
Dna Methyltransferase ◽  
Es Cells ◽  
Embryonic Stem ◽  
Dna Methyltransferase 1 ◽  
Biological Functions ◽  
Methylation Of Dna ◽  
Intracisternal A Particle ◽  
Genomic Methylation ◽  
Repressor Activity ◽  
Methyltransferase 1

ABSTRACT DNA methyltransferase 1 (DNMT1) has been reported to interact with a wide variety of factors and to contain intrinsic transcriptional repressor activity. When a conservative point mutation was introduced at the key catalytic residue, mutant DNMT1 failed to rescue any of the phenotypes of Dnmt1-null embryonic stem (ES) cells, which indicated that the biological functions of DNMT1 are exerted through the methylation of DNA. ES cells that expressed the mutant protein did not survive differentiation. Intracisternal A-particle family retrotransposons were no longer methylated and were transcribed at high levels. The proper localization of DNMT1 depended on normal genomic methylation, and we discuss the implications of this finding for epigenetic dysregulation in cancer.

scholarly journals Structural basis for Fullerene geometry in a human endogenous retrovirus capsid

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Oliver Acton ◽  
Tim Grant ◽  
Giuseppe Nicastro ◽  
Neil J. Ball ◽  
David C. Goldstone ◽  
...  
Keyword(s):  
Early Stage ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
Structural Basis ◽  
Human Endogenous Retrovirus ◽  
Structural Protein ◽  
Human Endogenous Retroviruses ◽  
Reading Frames

AbstractThe HML2 (HERV-K) group constitutes the most recently acquired family of human endogenous retroviruses, with many proviruses less than one million years old. Many maintain intact open reading frames and provirus expression together with HML2 particle formation are observed in early stage human embryo development and are associated with pluripotency as well as inflammatory disease, cancers and HIV-1 infection. Here, we reconstruct the core structural protein (CA) of an HML2 retrovirus, assemble particles in vitro and employ single particle cryogenic electron microscopy (cryo-EM) to determine structures of four classes of CA Fullerene shell assemblies. These icosahedral and capsular assemblies reveal at high-resolution the molecular interactions that allow CA to form both pentamers and hexamers and show how invariant pentamers and structurally plastic hexamers associate to form the unique polyhedral structures found in retroviral cores.

scholarly journals Molecular Cloning and Functional Analysis of Three Type D Endogenous Retroviruses of Sheep Reveal a Different Cell Tropism from That of the Highly Related Exogenous Jaagsiekte Sheep Retrovirus

2000 ◽  
Vol 74 (17) ◽  
pp. 8065-8076 ◽  
Author(s):  
Massimo Palmarini ◽  
Claus Hallwirth ◽  
Denis York ◽  
Claudio Murgia ◽  
Tulio de Oliveira ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
Lung Epithelial Cells ◽  
Structural Genes ◽  
Jaagsiekte Sheep Retrovirus ◽  
Type D ◽  
Viral Particles ◽  
Reading Frames

ABSTRACT Integrated into the sheep genome are 15 to 20 copies of type D endogenous loci that are highly related to two exogenous oncogenic viruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV). The exogenous viruses cause infectious neoplasms of the respiratory tract in small ruminants. In this study, we molecularly cloned three intact type D endogenous retroviruses of sheep (enJS56A1, enJS5F16, and enJS59A1; collectively called enJRSVs) and analyzed their genomic structures, their phylogenies with respect to their exogenous counterparts, their capacity to form viral particles, and the expression specificities of their long terminal repeats (LTRs). In addition, the pattern of expression of enJSRVs in vivo was studied by in situ hybridization. All of the threeenJSRV proviruses had open reading frames for at least one of the structural genes. In particular, enJS56A1 had open reading frames for all structural genes, but it could not assemble viral particles when highly expressed in human 293T cells. We localized the defect for viral assembly in the first two-thirds of thegag gene by making a series of chimeras between enJS56A1 and the exogenous infectious molecular clone JSRV21. Phylogenetic analysis distinguished five ovine type D retroviruses:enJSRV groups A and B, ENTV, and two exogenous JSRV groups (African versus United Kingdom/North America isolates). Transient transfection assays indicated that the LTRs of the threeenJSRVs were not preferentially active in differentiated lung epithelial cells. This suggests that the pulmonary tropic JSRV developed from a type D retrovirus that did not have lung specificity. Consistent with this, in situ hybridization of a panel of normal ovine tissues revealed high expression of enJSRV mRNA in the luminal epithelium and glandular epithelium of the uterus; lower expression was localized in the lamina propria of the gut and in the bronchiolar epithelium of the lungs.

scholarly journals A human ESC-based screen identifies a role for the translated lncRNA LINC00261 in pancreatic endocrine differentiation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Bjoern Gaertner ◽  
Sebastiaan van Heesch ◽  
Valentin Schneider-Lunitz ◽  
Jana Felicitas Schulz ◽  
Franziska Witte ◽  
...  
Keyword(s):  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Noncoding Rnas ◽  
Open Reading Frames ◽  
Developmentally Regulated ◽  
Pancreatic Differentiation ◽  
Endocrine Differentiation ◽  
Small Proteins ◽  
Heterogenous Group ◽  
Reading Frames

Long noncoding RNAs (lncRNAs) are a heterogenous group of RNAs, which can encode small proteins. The extent to which developmentally regulated lncRNAs are translated and whether the produced microproteins are relevant for human development is unknown. Using a human embryonic stem cell (hESC)-based pancreatic differentiation system, we show that many lncRNAs in direct vicinity of lineage-determining transcription factors (TFs) are dynamically regulated, predominantly cytosolic, and highly translated. We genetically ablated ten such lncRNAs, most of them translated, and found that nine are dispensable for pancreatic endocrine cell development. However, deletion of LINC00261 diminishes insulin+ cells, in a manner independent of the nearby TF FOXA2. One-by-one disruption of each of LINC00261's open reading frames suggests that the RNA, rather than the produced microproteins, is required for endocrine development. Our work highlights extensive translation of lncRNAs during hESC pancreatic differentiation and provides a blueprint for dissection of their coding and noncoding roles.

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