scholarly journals JUMP AROUND, JUMP AROUND: TRANSPOSABLE ELEMENT ACTIVATION IN NEURODEGENERATIVE TAUOPATHY

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S587-S587
Author(s):  
Bess E Frost ◽  
Wenyan Sun ◽  
Hanie Samimi ◽  
Habil Zare
Keyword(s):  
Transposable Elements ◽  
Transposable Element ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Element Mobilization ◽  
Cellular Defenses ◽  
Jumping Genes ◽  
The Brain ◽  
Transgenic Drosophila ◽  
Drosophila Models

Abstract Transposable elements, or “jumping genes,” constitute ~45% of the human genome. We have identified transposable element activation as a key mediator of neurodegeneration in tauopathies, a group of disorders that are pathologically defined by deposits of tau protein in the brain. Cellular defenses that limit transposable element mobilization include 1) formation of silencing heterochromatin and 2) generation of piwi-interacting RNAs (piRNAs) that clear transposable element transcripts. Using genetic approaches in Drosophila models of tauopathy, we find evidence for a causal relationship between tau-induced heterochromatin decondensation and piRNA depletion, transposable element mobilization, and neurodegeneration. 3TC, an FDA-approved inhibitor of reverse transcriptase, suppresses transposable element mobilization and neuronal death in tau transgenic Drosophila. We detect a significant increase in transcripts of the human endogenous retrovirus class of transposable elements in postmortem human Alzheimer’s disease brains. Our data identify transposable element activation as a conserved, pharmacologically targetable driver of neurodegeneration in tauopathy.

scholarly journals Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

2019 ◽  
Author(s):  
Paul Dembny ◽  
Andrew G. Newman ◽  
Manvendra Singh ◽  
Michael Hinz ◽  
Michal Szczepek ◽  
...  
Keyword(s):  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Endogenous Ligand ◽  
Human Endogenous Retroviruses ◽  
Retroviral Transcripts ◽  
The Brain ◽  
Deficient Mice

AbstractAlthough human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimer’s disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

Hinfp is a guardian of the somatic genome by repressing transposable elements

2021 ◽  
Vol 118 (41) ◽  
pp. e2100839118
Author(s):  
Niraj K. Nirala ◽  
Qi Li ◽  
Prachi N. Ghule ◽  
Hsi-Ju Chen ◽  
Rui Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transposable Elements ◽  
Transposable Element ◽  
Cancer Progression ◽  
Genome Stability ◽  
Genome Instability ◽  
Tissue Growth ◽  
Loss Of Function ◽  
Element Mobilization ◽  
Host Genes

Germ cells possess the Piwi-interacting RNA pathway to repress transposable elements and maintain genome stability across generations. Transposable element mobilization in somatic cells does not affect future generations, but nonetheless can lead to pathological outcomes in host tissues. We show here that loss of function of the conserved zinc-finger transcription factor Hinfp causes dysregulation of many host genes and derepression of most transposable elements. There is also substantial DNA damage in somatic tissues of Drosophila after loss of Hinfp. Interference of transposable element mobilization by reverse-transcriptase inhibitors can suppress some of the DNA damage phenotypes. The key cell-autonomous target of Hinfp in this process is Histone1, which encodes linker histones essential for higher-order chromatin assembly. Transgenic expression of Hinfp or Histone1, but not Histone4 of core nucleosome, is sufficient to rescue the defects in repressing transposable elements and host genes. Loss of Hinfp enhances Ras-induced tissue growth and aging-related phenotypes. Therefore, Hinfp is a physiological regulator of Histone1-dependent silencing of most transposable elements, as well as many host genes, and serves as a venue for studying genome instability, cancer progression, neurodegeneration, and aging.

scholarly journals Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system

2021 ◽  
Author(s):  
Paulino Ramirez ◽  
Wenyan Sun ◽  
Gabrielle Zuniga ◽  
Elizabeth Ochoa Thomas ◽  
Sarah L. DeVos ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Transgenic Mice ◽  
Transposable Elements ◽  
Transposable Element ◽  
Mouse Brain ◽  
Brain Aging ◽  
Endogenous Retrovirus ◽  
Highly Active ◽  
Intracisternal A Particle ◽  
Mouse Central Nervous System

ABSTRACTTransposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer disease and related tauopathies, and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class of retrotransposons is particularly enriched. We show that protein encoded by Intracisternal A-particle, a highly active mouse ERV, is elevated in brains of tau transgenic mice. We further demonstrate that brains of tau transgenic mice contain increased DNA copy number of transposable elements, raising the possibility that these elements actively retrotranspose in the context of tauopathy. Taken together, our study lays the groundwork for future mechanistic studies focused on transposable element regulation in the aging mouse brain and in mouse models of tauopathy, while providing support for therapeutic approaches targeting transposable element activation for Alzheimer disease and related tauopathies.

Evidence for a functional subclass of the RTVL-H family of human endogenous retrovirus-like sequences.

1993 ◽  
Vol 67 (6) ◽  
pp. 2981-2989 ◽  
Author(s):  
D A Wilkinson ◽  
N L Goodchild ◽  
T M Saxton ◽  
S Wood ◽  
D L Mager
Keyword(s):  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus

Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients

Epigenomics ◽  
2020 ◽  
Vol 12 (19) ◽  
pp. 1689-1706
Author(s):  
Maurizio Cardelli ◽  
Remco van Doorn ◽  
Lares Larcher ◽  
Michela Di Donato ◽  
Francesco Piacenza ◽  
...  
Keyword(s):  
Independent Predictor ◽  
Disease Free Survival ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Free Survival ◽  
Melanocytic Lesions ◽  
Long Interspersed Nuclear Elements ◽  
Melanoma Patients ◽  
And Gender ◽  
Disease Free

Aim: To evaluate CpG methylation of long interspersed nuclear elements 1 (LINE-1) and human endogenous retrovirus K (HERV-K) retroelements as potential prognostic biomarkers in cutaneous melanoma. Materials & methods: Methylation of HERV-K and LINE-1 retroelements was assessed in resected melanoma tissues from 82 patients ranging in age from 14 to 88 years. In addition, nevi from eight patients were included for comparison with nonmalignant melanocytic lesions. Results: Methylation levels were lower in melanomas than in nevi. HERV-K and LINE-1 methylation were decreased in melanoma patients with clinical parameters associated with adverse prognosis, while they were independent of age and gender. Hypomethylation of HERV-K (but not LINE-1) was an independent predictor of reduced disease-free survival. Conclusion: HERV-K hypomethylation can be a potential independent biomarker of melanoma recurrence.

scholarly journals HERV-K Gag RNA and Protein Levels Are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 449
Author(s):  
Simin D. Rezaei ◽  
Joshua A. Hayward ◽  
Sam Norden ◽  
John Pedersen ◽  
John Mills ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Normal Prostate ◽  
Tissue Samples ◽  
Gag Protein ◽  
Protein Levels ◽  
Prostate Epithelial Cells ◽  
Prostate Cancers

Heightened expression of human endogenous retrovirus (HERV) sequences has been associated with a range of malignancies, including prostate cancer, suggesting that they may serve as useful diagnostic or prognostic cancer biomarkers. We analysed the expression of HERV-K (Gag and Env/Np9 regions), HERV-E 4.1 (Pol and Env regions), HERV-H (Pol) and HERV-W (Gag) sequences in prostate cancer cells lines and normal prostate epithelial cells using qRT-PCR. HERV expression was also analysed in matched malignant and benign prostate tissue samples from men with prostate cancer (n = 27, median age 65.2 years (range 47–70)) and compared to prostate cancer-free male controls (n = 11). Prostate cancer epithelial cell lines exhibited a signature of HERV RNA overexpression, with all HERVs analysed, except HERV-E Pol, showing heightened expression in at least two, but more commonly all, cell lines analysed. Analysis of primary prostate material indicated increased expression of HERV-E Pol but decreased expression of HERV-E Env in both malignant and benign regions of the prostate in men with prostate cancer as compared to those without. Expression of HERV-K Gag was significantly higher in malignant regions of the prostate in men with prostate cancer as compared to matched benign regions and prostate cancer-free men (p < 0.001 for both), with 85.2% of prostate cancers donors showing malignancy-associated upregulation of HERV-K Gag RNA. HERV-K Gag protein was detected in 12/18 (66.7%) malignant tissues using immunohistochemistry, but only 1/18 (5.6%) benign tissue sections. Heightened expression of HERV-K Gag RNA and protein appears to be a sensitive and specific biomarker of prostate malignancy in this cohort of men with prostate carcinoma, supporting its potential utility as a non-invasive, adjunct clinical biomarker.

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.

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