Mechanisms of HERV-K (HML-2) transcription during human mammary epithelial cell transformation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84275 | GEO | 2017/10/13
SECONDARY ACCESSION(S): PRJNA328504
REPOSITORIES: GEO
Similar Datasets
Project description:The biological function and disease association of human endogenous retroviral (HERV) elements remains largely elusive. We addressed the physiological role of HERV-K(HML-2) in neuronal differentiation by manipulating HERV-K(HML-2) expression levels. We used CRISPR engineering to activate or repress HERV-K(HML-2) and demonstrate that elevated HERV-K(HML-2) transcription is detrimental for development, functionality and growth of cortical neurons. Effects are cell-type specific, as dopaminergic neurons were unaffected. We further show that layer formation is altered during forebrain organoid formation following activation of HERV-K(HML-2) transcription. HERV-K(HML-2) transcriptional activation concurrently elevated Neurotrophic Tyrosine Receptor Kinase 3 (NTRK3) expression along with other neurodegeneration-related genes. Direct transcriptional activation of NTRK3 resembled the HERV-K(HML-2) activation phenotype. Intriguingly, reduction of NTRK3 levels in HERV-K(HML-2)-activated cortical neurons restored differentiated cortical neurons. Hence, our findings unravel a unique cell type-specific mechanism of HERV-K(HML-2) during cortical neuronal differentiation.
2021-03-30 | GSE171101 | GEO
Project description: Not available
| S-EPMC5730778 | biostudies-literature
Project description:Identification of transcribed HERV-K(HML-2) loci in amyotrophic lateral sclerosis
| PRJEB23125 | ENA
Project description:The human genome consists of considerable portions derived from retroviruses typically inherited already for millions of years. So-called human endogenous retroviruses (HERVs) are usually severely mutated, yet some coding-competent HERV sequences exist. The HERV-K(HML-2) group includes evolutionarily young proviruses that still encode typical retroviral proteins. HERV-K(HML-2) has been implicated in various human diseases because transcription is often upregulated and encoded proteins are known to affect cell biology. HERV-K(HML-2) protease has received little attention so far. With findings for Human Immunodeficiency Virus (HIV) protease in mind we set out to identify human cellular proteins being substrates of HERV-K(HML-2) protease employing a modified Terminal Amine Isotopic Labeling of Substrates (TAILS) procedure. Thousands of significantly processed human proteins were revealed by TAILS and we could verify cleavage of a majority of selected human proteins in vitro. Our analysis suggests that hundreds, if not thousands of cellular proteins are potential substrates of HERV-K(HML-2) protease. As identified proteins participate in diverse, often disease-relevant cellular processes, it is conceivable that expression of HERV-K(HML-2) protease has functional consequences for cell biology and thus development of human diseases. Endogenous retrovirus-encoded protease may also be relevant for disease development in species other than human.
2019-09-02 | PXD010159 | Pride
Project description:Background: The human genome consists of considerable portions derived from retroviruses inherited for millions of years. So-called human endogenous retroviruses (HERVs) are usually severely mutated, yet some coding-competent HERVs exist. The HERV-K(HML-2) group includes evolutionarily young proviruses that still encode typical retroviral proteins. HERV-K(HML-2) has been implicated in various human diseases because transcription is often upregulated and some of the encoded proteins are known to affect cell biology. HERV-K(HML-2) Protease (Pro) has received little attention so far, although it appears expressed in some disease contexts and other retroviral proteases are known to process cellular proteins. Results: We set out to identify human cellular proteins being substrates of HERV-K(HML-2) Pro employing a modified Terminal Amine Isotopic Labeling of Substrates (TAILS) procedure. Thousands of human proteins were identified as significantly processed by HERV-K(HML-2) Pro. Identified proteins locate to various cellular compartments and participate in diverse, often disease-relevant cellular processes. We verified cleavage of a majority of selected human proteins in vitro and in vivo. Conclusions: Hundreds, if not thousands of cellular proteins are potential substrates of HERV-K(HML-2) Pro. It is conceivable that even low-level expression of HERV-K(HML-2) Pro has a functional impact on cell biology and thus relevance for human diseases. Specific studies will be required to elucidate effects of HERV-K(HML-2) Pro expression regarding human substrate proteins, cell biology and disease. Endogenous retrovirus-encoded Pro activity may also be relevant for disease development in species other than human.
2019-09-02 | PXD013296 | Pride
Project description:The endogenous retrovirus type W (HERV-W) is a human specific entity, which was initially discovered in multiple sclerosis (MS) patient derived cells. We initially found that the HERV-W envelope (ENV) protein negatively affects oligodendrogenesis and controls microglial cell polarization towards a myelinated axon associated and damaging phenotype. Such first functional assessments were conducted ex vivo, given the human specific origin of HERV-W. Recent experimental evidence gathered on a novel transgenic mouse model, mimicking activation and expression of the HERV-W ENV protein, revealed that all glial cell types are impacted and that cellular fates, differentiation, and functions were changed. In order to identify a HERV-W specific signature in glial cells, the current study analyzed the transcriptome of ENV stimulated microglial- and astroglial cells and compared the transcriptomic signature to lipopolysaccharide (LPS) stimulated cells, owing to the fact that both ligands can activate toll-like receptor-4 (TLR-4). Additionally, a comparison between published disease associated glial signatures and the transcriptome of HERV-W ENV stimulated glial cells was conducted. We, therefore, provide here for the first time a detailed molecular description of specific HERV-W ENV evoked effects on those glial cell populations that are involved in smoldering neuroinflammatory processes relevant for progression of neurodegenerative diseases.
2024-03-30 | GSE262029 | GEO
Project description:Human Endogenous Retroviruses (HERVs) are exogenous viral elements that integrated into the germline millions of years ago. They comprise 8% of the human genome and play a critical role in cellular differentiation during development. HERV-K(HML-2) is the most recently integrated and actively transcribed HERV. It is found to be highly expressed in pluripotent stem cells and strongly downregulated during cellular differentiation. Moreover, expression of HERV-K in terminally differentiated neurons results in cytotoxicity. Expression of HERVs has been implicated in carcinogenesis and is suggested to confer stem cell like features important for cell growth. Atypical Teratoid / Rhabdoid Tumor (AT/RT) is a rare pediatric brain cancer that results from incomplete neuronal differentiation during embryonic development. In this paper, we investigated the cytopathic effect of Ouabain, a cardiac glycoside that induces cytotoxicity in stem cells, on AT/RT cells. We characterized four AT/RT cell lines by immunostaining and observed variable levels of stem cell, Oct4 and Pax6, and neuronal differentiation markers, TUBB3 and MAP2, as well as HERV-K envelope (env), polymerase (pol), and gag transcripts. We stained formalin-fixed brain tissues from 20 AT/RT patients and 5 unaffected controls for HERV-K ENV protein expression. 40% of AT/RT patient tissues showed ENV expression. In contrast, no ENV immunostaining was observed in all 5 control brain tissues. We used Ouabain, known to be cytotoxic to stem cells, observed up to 50% toxicity at 24 hr and 80% toxicity at 48 hr after treatment. While AT/RT primarily exist as large cell aggregates in suspension, Ouabain treatment downregulated HERV-K ENV protein and caused disruption of cell-to-cell interactions. Similarly, when AT/RT cells were transfected with a CRISPR/Cas9 construct designed to repress HERV-K promotor activity, cell aggregates separated and cell viability decreased significantly. Using a luciferase reporter construct under the control of a HERV-K promotor, we observed a significant decrease in HERV-K promotor activity at 8 to 72 hr post treatment with 0.5 uM Ouabain. Given that downregulation of HERV-K alone was sufficient to cause cytotoxicity in the cells, HERV-K expression may be essential for AT/RT growth and survival. Ouabain and other compounds that modulate HERV expression may provide an alternative or adjunctive therapeutic option for treatment of embryonal tumors.
2021-06-28 | GSE124210 | GEO
Project description:The HERV-K(HML2) family is a group of elements of retroviral origin that are present in the human genome. They are silenced in most normal tissues, but are induced in a number of human cancers. In order to assess the relevance of their expression in these pathologies, the consequences of ectopic expression of the HERV-K(HML2) envelope protein were analysed in human 293T cells. The cells were transfected with a control vector, or an expression vector for the HERV-K(HML2) envelope protein. Total RNA was extracted 24h and 48h post transfection, and duplicate samples were analysed on whole genome transcriptional microarrays.
2017-06-17 | E-MTAB-5509 | biostudies-arrayexpress
Project description:Activation of HERV-K(HML-2) limits cortical neuronal differentiation by modulating Neurotrophic Tyrosine Receptor Kinase 3 expression
| PRJNA718326 | ENA