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Human Endogenous Retrovirus-K in Stem Cell Function and Neuronal Differentiation [dataset 1]

ABSTRACT: Human endogenous retrovirus (HERV) genes were incorporated into the genome over millions of years but they mostly have inactivating mutations. HERV-K is the most recently incorporated virus. Incidental HERV-K gene expression occurs in a variety of pathological conditions. However, its physiological role is poorly understood. To study the role of HERV-K in development, we monitored its expression and function in pluripotent stem cells and during the process of neuronal differentiation. The expression of HERV-K env was localized to chromosomes 12 and 19. HERV-K Env was expressed on the cell surface of pluripotent stem cells and was critical in maintaining the stemness and adhesion of the cells. Interactions with CD98HC resulted in activation of signaling pathways that regulate stem cells genes. Down regulation of HERV-K env resulted in dissociation of the stem cell colonies and enhanced differentiation along neuronal pathways. HERV-K env expression during neurodevelopment was regulated by DNA methylation. Thus HERV-K regulation is critical for human embryonic and neurodevelopment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110267 | GEO | 2020/08/05

REPOSITORIES: GEO

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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.

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Human Endogenous Retrovirus-K in Stem Cell Function and Neuronal Differentiation [dataset 1]

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