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Age- and disease-dependent HERV-W envelope allelic variation in brain: association with neuroimmune gene expression.

ABSTRACT: BACKGROUND: The glycoprotein, Syncytin-1, is encoded by a human endogenous retrovirus (HERV)-W env gene and is capable of inducing neuroinflammation. The specific allele(s) responsible for Syncytin-1 expression in the brain is uncertain. Herein, HERV-W env diversity together with Syncytin-1 abundance and host immune gene profiles were examined in the nervous system using a multiplatform approach. RESULTS: HERV-W env sequences were encoded by multiple chromosomal encoding loci in primary human neurons compared with less chromosomal diversity in astrocytes and microglia (p<0.05). HERV-W env RNA sequences cloned from brains of patients with systemic or neurologic diseases were principally derived from chromosomal locus 7q21.2. Within the same specimens, HERV-W env transcript levels were correlated with the expression of multiple proinflammatory genes (p<0.05). Deep sequencing of brain transcriptomes disclosed the env transcripts to be the most abundant HERV-W transcripts, showing greater expression in fetal compared with healthy adult brain specimens. Syncytin-1's expression in healthy brain specimens was derived from multiple encoding loci and linked to distinct immune and developmental gene profiles. CONCLUSIONS: Syncytin-1 expression in the brain during disease was associated with neuroinflammation and was principally encoded by a full length provirus. The present studies also highlighted the diversity in HERV gene expression within the brain and reinforce the potential contributions of HERV expression to neuroinflammatory diseases.

SUBMITTER: Bhat RK

PROVIDER: S-EPMC3084769 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Age- and disease-dependent HERV-W envelope allelic variation in brain: association with neuroimmune gene expression.

Bhat Rakesh K RK Ellestad Kristofor K KK Wheatley B Matt BM Warren Rene R Holt Robert A RA Power Christopher C

PloS one 20110429 4

<h4>Background</h4>The glycoprotein, Syncytin-1, is encoded by a human endogenous retrovirus (HERV)-W env gene and is capable of inducing neuroinflammation. The specific allele(s) responsible for Syncytin-1 expression in the brain is uncertain. Herein, HERV-W env diversity together with Syncytin-1 abundance and host immune gene profiles were examined in the nervous system using a multiplatform approach.<h4>Results</h4>HERV-W env sequences were encoded by multiple chromosomal encoding loci in pri ...[more]

PMID: 21559469

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Project description:Measuring allelic RNA expression ratios is a powerful approach for detecting cis-acting regulatory variants, RNA editing, loss of heterozygosity in cancer, copy number variation, and allele-specific epigenetic gene silencing. Whole transcriptome RNA sequencing (RNA-Seq) has emerged as a genome-wide tool for identifying allelic expression imbalance (AEI), but numerous factors bias allelic RNA ratio measurements. Here, we compare RNA-Seq allelic ratios measured in nine different human brain regions with a highly sensitive and accurate SNaPshot measure of allelic RNA ratios, identifying factors affecting reliable allelic ratio measurement. Accounting for these factors, we subsequently surveyed the variability of RNA editing across brain regions and across individuals.We find that RNA-Seq allelic ratios from standard alignment methods correlate poorly with SNaPshot, but applying alternative alignment strategies and correcting for observed biases significantly improves correlations. Deploying these methods on a transcriptome-wide basis in nine brain regions from a single individual, we identified genes with AEI across all regions (SLC1A3, NHP2L1) and many others with region-specific AEI. In dorsolateral prefrontal cortex (DLPFC) tissues from 14 individuals, we found evidence for frequent regulatory variants affecting RNA expression in tens to hundreds of genes, depending on stringency for assigning AEI. Further, we find that the extent and variability of RNA editing is similar across brain regions and across individuals.These results identify critical factors affecting allelic ratios measured by RNA-Seq and provide a foundation for using this technology to screen allelic RNA expression on a transcriptome-wide basis. Using this technology as a screening tool reveals tens to hundreds of genes harboring frequent functional variants affecting RNA expression in the human brain. With respect to RNA editing, the similarities within and between individuals leads us to conclude that this post-transcriptional process is under heavy regulatory influence to maintain an optimal degree of editing for normal biological function.

Project description:Endogenous retroviruses are the remnants of past retroviral infections that are scattered within mammalian genomes. In humans, most of these elements are old degenerate sequences that have lost their coding properties. The HERV-K(HML2) family is an exception: it recently amplified in the human genome and corresponds to the most active proviruses, with some intact open reading frames and the potential to encode viral particles. Here, using a reconstructed consensus element, we show that HERV-K(HML2) proviruses are able to inhibit Tetherin, a cellular restriction factor that is active against most enveloped viruses and acts by keeping the viral particles attached to the cell surface. More precisely, we identify the Envelope protein (Env) as the viral effector active against Tetherin. Through immunoprecipitation experiments, we show that the recognition of Tetherin is mediated by the surface subunit of Env. Similar to Ebola glycoprotein, HERV-K(HML2) Env does not mediate Tetherin degradation or cell surface removal; therefore, it uses a yet-undescribed mechanism to inactivate Tetherin. We also assessed all natural complete alleles of endogenous HERV-K(HML2) Env described to date for their ability to inhibit Tetherin and found that two of them (out of six) can block Tetherin restriction. However, due to their recent amplification, HERV-K(HML2) elements are extremely polymorphic in the human population, and it is likely that individuals will not all possess the same anti-Tetherin potential. Because of Tetherin's role as a restriction factor capable of inducing innate immune responses, this could have functional consequences for individual responses to infection.Tetherin, a cellular protein initially characterized for its role against HIV-1, has been proven to counteract numerous enveloped viruses. It blocks the release of viral particles from producer cells, keeping them tethered to the cell surface. Several viruses have developed strategies to inhibit Tetherin activity, allowing them to efficiently infect and replicate in their host. Here, we show that human HERV-K(HML2) elements, the remnants of an ancient retroviral infection, possess an anti-Tetherin activity which is mediated by the envelope protein. It is likely that this activity was an important factor that contributed to the recent, human-specific amplification of this family of elements. Also, due to their recent amplification, HERV-K(HML2) elements are highly polymorphic in the human population. Since Tetherin is a mediator of innate immunity, interindividual variations among HERV-K(HML2) Env genes may result in differences in immune responses to infection.

Dataset Information

Age- and disease-dependent HERV-W envelope allelic variation in brain: association with neuroimmune gene expression.

Publications

Age- and disease-dependent HERV-W envelope allelic variation in brain: association with neuroimmune gene expression.

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