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

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.

Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types.

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors.

Integrin-Linked Kinase Mediates Therapeutic Resistance of Quiescent CML Stem Cells to Tyrosine Kinase Inhibitors.

Patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs) due to a persisting TKI-resistant population of leukemic stem cells (LSCs). From transcriptome profiling, we show integrin-linked kinase (ILK), a key constituent of focal adhesions, is highly expressed in TKI-nonresponsive patient cells and their LSCs. Genetic and pharmacological inhibition of ILK impaired the survival of nonresponder patient cells, sensitizing them to TKIs, even in the presence of protective niche cells.

Loss of macpΨ Ribosomal RNA Modification Is a Major Feature of Cancer.

The ribosome is an RNA-protein complex that is essential for translation in all domains of life. The structural and catalytic core of the ribosome is its ribosomal RNA (rRNA). While mutations in ribosomal protein (RP) genes are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive.

Reality check for transposon enhancers.

Hundreds of retrovirus-like sequences have features that suggest they might be gene enhancers, but only a small fraction displays gene-regulating activity in experiments on mouse stem cells.

Mouse germ line mutations due to retrotransposon insertions.

Transposable element (TE) insertions are responsible for a significant fraction of spontaneous germ line mutations reported in inbred mouse strains. This major contribution of TEs to the mutational landscape in mouse contrasts with the situation in human, where their relative contribution as germ line insertional mutagens is much lower. In this focussed review, we provide comprehensive lists of TE-induced mouse mutations, discuss the different TE types involved in these insertional mutations and elaborate on particularly interesting cases.

LIONS: analysis suite for detecting and quantifying transposable element initiated transcription from RNA-seq.

Summary: Transposable elements (TEs) influence the evolution of novel transcriptional networks yet the specific and meaningful interpretation of how TE-derived transcriptional initiation contributes to the transcriptome has been marred by computational and methodological deficiencies. We developed LIONS for the analysis of RNA-seq data to specifically detect and quantify TE-initiated transcripts.

Availability And Implementation: Source code, container, test data and instruction manual are freely available at www.

Ten things you should know about transposable elements.

Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remain a matter of intense interrogation. The rise of genomics and large-scale functional assays has shed new light on the multi-faceted activities of TEs and implies that they should no longer be marginalized.

A novel isoform of IL-33 revealed by screening for transposable element promoted genes in human colorectal cancer.

Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences contain multiple regulatory motifs and hence are capable of influencing expression of host genes. TEs are known to be released from epigenetic repression and can become transcriptionally active in cancer.

Epigenetic modifier drugs trigger widespread transcription of endogenous retroviruses.

A study in this issue demonstrates that epigenome-modifying drugs used in cancer chemotherapy induce transcription from thousands of previously unannotated transcription start sites, most of which are derived from ancient endogenous retroviruses (ERVs). This work, coupled with previous related findings, suggests that induction of ERVs, rather than direct effects on specific genes, may have a central role in the cellular responses to such agents and, in turn, their therapeutic efficacy.

Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity.

A number of chemical compounds have been shown to induce liver tumors in mice but not in other species. While several mechanisms for this species-specific tumorigenicity have been proposed, no definitive mechanism has been established. We examined the effects of the nongenotoxic rodent hepatic carcinogen, WY-14,643, in male mice from a high liver tumor susceptible strain (C3H/HeJ), and from a low tumor susceptible strain (C57BL/6).

Endogenous retroviral promoter exaptation in human cancer.

Cancer arises from a series of genetic and epigenetic changes, which result in abnormal expression or mutational activation of oncogenes, as well as suppression/inactivation of tumor suppressor genes. Aberrant expression of coding genes or long non-coding RNAs (lncRNAs) with oncogenic properties can be caused by translocations, gene amplifications, point mutations or other less characterized mechanisms. One such mechanism is the inappropriate usage of normally dormant, tissue-restricted or cryptic enhancers or promoters that serve to drive oncogenic gene expression.

Transposable elements in the mammalian embryo: pioneers surviving through stealth and service.

Transposable elements (TEs) are notable drivers of genetic innovation. Over evolutionary time, TE insertions can supply new promoter, enhancer, and insulator elements to protein-coding genes and establish novel, species-specific gene regulatory networks. Conversely, ongoing TE-driven insertional mutagenesis, nonhomologous recombination, and other potentially deleterious processes can cause sporadic disease by disrupting genome integrity or inducing abrupt gene expression changes.

Pluripotency and the endogenous retrovirus HERVH: Conflict or serendipity?

Remnants of ancient retroviral infections during evolution litter all mammalian genomes. In modern humans, such endogenous retroviral (ERV) sequences comprise at least 8% of the genome. While ERVs and other types of transposable elements undoubtedly contribute to the genomic "junk yard", functions for some ERV sequences have been demonstrated, with growing evidence that ERVs can be important players in gene regulatory processes.

Mammalian Endogenous Retroviruses.

Over 40% of mammalian genomes comprise the products of reverse transcription. Among such retrotransposed sequences are those characterized by the presence of long terminal repeats (LTRs), including the endogenous retroviruses (ERVs), which are inherited genetic elements closely resembling the proviruses formed following exogenous retrovirus infection. Sequences derived from ERVs make up at least 8 to 10% of the human and mouse genomes and range from ancient sequences that predate mammalian divergence to elements that are currently still active.

Epigenetic mechanism causes Wnt9b deficiency and nonsyndromic cleft lip and palate in the A/WySn mouse strain.

Background: The heritable multifactorial etiology of human nonsyndromic cleft lip with or without cleft palate (CL ± P) is not understood. CL ± P occurs in 15% of neonates in the homozygous A/WySn mouse strain, with a multifactorial genetic etiology, the clf1 and clf2 variant genes. Clf1 acts as a mutant allele of Wnt9b but its coding sequence is normal.

Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma.

Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences harbor multiple regulatory motifs and hence are capable of influencing expression of host genes. In response to environmental changes, TEs are known to be released from epigenetic repression and to become transcriptionally active.

Genistein versus ICI 182, 780: an ally or enemy in metastatic progression of prostate cancer.

Background: Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen in synergy with androgen is essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen and the estrogen receptor play in prostate carcinogenesis remains unclear.

Visualized computational predictions of transcriptional effects by intronic endogenous retroviruses.

When endogenous retroviruses (ERVs) or other transposable elements (TEs) insert into an intron, the consequence on gene transcription can range from negligible to a complete ablation of normal transcripts. With the advance of sequencing technology, more and more insertionally polymorphic or private TE insertions are being identified in humans and mice, of which some could have a significant impact on host gene expression. Nevertheless, an efficient and low cost approach to prioritize their potential effect on gene transcription has been lacking.

Epigenetic interplay between mouse endogenous retroviruses and host genes.

Background: Transposable elements are often the targets of repressive epigenetic modifications such as DNA methylation that, in theory, have the potential to spread toward nearby genes and induce epigenetic silencing. To better understand the role of DNA methylation in the relationship between transposable elements and genes, we assessed the methylation state of mouse endogenous retroviruses (ERVs) located near genes.

Results: We found that ERVs of the ETn/MusD family show decreased DNA methylation when near transcription start sites in tissues where the nearby gene is expressed.

Transposable elements: an abundant and natural source of regulatory sequences for host genes.

The fact that transposable elements (TEs) can influence host gene expression was first recognized more than 50 years ago. However, since that time, TEs have been widely regarded as harmful genetic parasites-selfish elements that are rarely co-opted by the genome to serve a beneficial role. Here, we survey recent findings that relate to TE impact on host genes and remind the reader that TEs, in contrast to other noncoding parts of the genome, are uniquely suited to gene regulatory functions.

Transposable elements: not as quiet as a mouse.

In this issue of Genome Biology, Nellåker et al. show massive purging of deleterious transposable element variants, through negative selection, in 18 mouse strains.

C-GATE - catalogue of genes affected by transposable elements.

Background: Functional regulatory sequences are present in many transposable element (TE) copies, resulting in TEs being frequently exapted by host genes. Today, many examples of TEs impacting host gene expression can be found in the literature and we believe a new catalogue of such exaptations would be useful for the field.

Findings: We have established the catalogue of genes affected by transposable elements (C-GATE), which can be found at https://sites.