Endogenous Retroviral Elements in Human Development and Central Nervous System Embryonal Tumors

Doucet-O’Hare, Tara T.; Rosenblum, Jared S.; Shah, Ashish H.; Gilbert, Mark R.; Zhuang, Zhengping

doi:10.3390/jpm11121332

Cited by 3 publications

(1 citation statement)

References 51 publications

(111 reference statements)

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“…Human endogenous retroviruses (HERVs) are remnants of ancient infection by retroviruses, comprising nearly 8% of the human genome (Deniz et al, 2018; Durnaoglu et al, 2021a; Geis and Goff, 2020; Groh and Schotta, 2017; Liu et al, 2014; Mao et al, 2021). Whereas most HERVs are permanently inactivated by accumulated mutations or strongly suppressed by epigenetic machineries, some of the activation-competent copies of HERVs may play critical roles in a wide variety of human diseases, including various malignancies, autoimmune diseases, and neurological disorders (Babaian and Mager, 2016; Doucet-O’Hare et al, 2021). Non-physiological reactivation of HERVs may be caused by malnutrition, exposure to environmental toxicants, or impaired health conditions (Sakurai et al, 2019; Sharif et al, 2013; Shioda et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Viral proteins and virus-like particles of the LTR5_Hs endogenous retrovirus in human primordial germ cell-like cells

Kobayashi

Kreuzer

et al. 2022

Preprint

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The hominoid-specific endogenous retrovirus LTR5_Hs is transcriptionally activated in human primordial germ cell-like cells (hPGCLCs), a pluripotent stem cell-derived cell culture model of PGCs. Here, taking the unique advantage of our novel cell culture method to obtain large amounts of pure hPGCLCs, we performed proteomics profiling of hPGCLCs and detected various viral proteins produced from the LTR5_Hs RNA via ribosomal frameshifting. We also present transmission electron microscopy images of 100-nm diameter virus-like particles (VLPs) assembled at the surface of hPGCLCs. Compared to hPGCLCs, expression of LTR5_Hs RNA is far weaker in human seminomas, the germ cell tumors resembling PGCs. Re-analysis of published single cell RNA-seq data of human embryos revealed strong activation of LTR5_Hs in migrating PGCs but suppressed in PGCs upon they reach the gonadal anlagen. In the microfluidics-supported polarized embryoids mimicking peri-implantation stages of human embryos, LTR5_Hs RNA was detected by RNA in situ hybridization in NANOG+/TFAP2C+/SOX17+ cells resembling freshly emerged PGCs. These results support that human germ cells produce LTR5_Hs proteins and VLPs during their earliest stages of normal development until their settlement in the gonadal anlagen.

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Section: Introductionmentioning

confidence: 99%

Viral proteins and virus-like particles of the LTR5_Hs endogenous retrovirus in human primordial germ cell-like cells

Kobayashi

Kreuzer

et al. 2022

Preprint

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Does the interplay between human endogenous retrovirus K and extracellular vesicles contribute to aging?

DeMarino,

Nath,

Zhuang

et al. 2023

Extracell Vesicles Circ Nucleic Acids

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The role of extracellular vesicles (EVs), including retroviral-like particles (RVLPs), in pathogenic processes is currently a subject of active investigation. Several studies have identified mechanistic links between the increased presence of EVs and the process of senescence. A recent study reveals that the reverse transcribed complementary DNA (cDNA) of a human endogenous retroviral sequence can activate the innate immune system and result in tissue damage and/or the spread of cellular senescence to distant tissues. Several studies have linked EVs to age-related diseases, such as Alzheimer’s disease and Parkinson’s disease, and have included isolation of EVs from individuals with these diseases. Loss of epigenetic regulation, immune activation, and environmental stimuli can all lead to the expression of endogenous retroviruses and the incorporation of their proteins and transcripts into EVs. In addition, EVs disseminating these endogenous retroviral components have now been shown to act in a paracrine manner in multiple human diseases. Further investigation of the connection between EVs containing endogenous retroviral protein products or nucleotides should be pursued in models of age-related diseases.

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Epigenetic Regulation in Primary CNS Tumors: An Opportunity to Bridge Old and New WHO Classifications

Dang

Rosenblum

Shah

et al. 2023

Cancers

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Originally approved in 1979, a specific grading classification for central nervous system (CNS) tumors was devised by the World Health Organization (WHO) in an effort to guide cancer treatment and better understand prognosis. These “blue books” have since undergone several iterations based on tumor location, advancements in histopathology, and most recently, diagnostic molecular pathology in its fifth edition. As new research methods have evolved to elucidate complex molecular mechanisms of tumorigenesis, a need to update and integrate these findings into the WHO grading scheme has become apparent. Epigenetic tools represent an area of burgeoning interest that encompasses all non-Mendelian inherited genetic features affecting gene expression, including but not limited to chromatin remodeling complexes, DNA methylation, and histone regulating enzymes. The SWItch/Sucrose non-fermenting (SWI/SNF) chromatin remodeling complex is the largest mammalian family of chromatin remodeling proteins and is estimated to be altered in 20–25% of all human malignancies; however, the ways in which it contributes to tumorigenesis are not fully understood. We recently discovered that CNS tumors with SWI/SNF mutations have revealed an oncogenic role for endogenous retroviruses (ERVs), remnants of exogenous retroviruses that integrated into the germline and are inherited like Mendelian genes, several of which retain open reading frames for proteins whose expression putatively contributes to tumor formation. Herein, we analyzed the latest WHO classification scheme for all CNS tumors with documented SWI/SNF mutations and/or aberrant ERV expression, and we summarize this information to highlight potential research opportunities that could be integrated into the grading scheme to better delineate diagnostic criteria and therapeutic targets.

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Endogenous Retroviral Elements in Human Development and Central Nervous System Embryonal Tumors

Cited by 3 publications

References 51 publications

Viral proteins and virus-like particles of the LTR5_Hs endogenous retrovirus in human primordial germ cell-like cells

Viral proteins and virus-like particles of the LTR5_Hs endogenous retrovirus in human primordial germ cell-like cells

Does the interplay between human endogenous retrovirus K and extracellular vesicles contribute to aging?

Epigenetic Regulation in Primary CNS Tumors: An Opportunity to Bridge Old and New WHO Classifications

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