The LTR enhancer of ERV-9 human endogenous retrovirus is active in oocytes and progenitor cells in transgenic zebrafish and humans

Abstract

The solitary LTRs of ERV-9 human endogenous retrovirus are middle repetitive DNAs associated with 3,000 -4,000 human gene loci including the ␤-globin gene locus where the ERV-9 LTR is juxtaposed to the locus control region (␤-LCR) far upstream of the globin genes. The ERV-9 LTRs are conserved during primate evolution, but their function in the primate genomes is unknown. Here, we show that in transgenic zebrafish harboring the ␤-globin ERV-9 LTR coupled to the GFP gene, the LTR enhancer was active and initiated synthesis of GFP mRNA in oocytes but not in spermatozoa, and GFP expression in the embryos was maternally inherited. The LTR enhancer was active also in stem͞ progenitor cell regions of adult tissues of transgenic zebrafish. In human tissues, ERV-9 LTR enhancer was active also in oocytes and stem͞progenitor cells but not in spermatozoa and a number of differentiated, adult somatic cells. Transcriptional analyses of the human ␤-globin gene locus showed that the ␤-globin ERV-9 LTR enhancer initiated RNA synthesis from the LTR in the direction of the downstream ␤ locus control region and globin genes in ovary and erythroid progenitor cells. The findings suggest that, during oogenesis, ERV-9 LTR enhancers in the human genome could activate the cis-linked gene loci to synthesize maternal mRNAs required for early embryogenesis. Alternatively, the ERV-9 LTR enhancers, in initiating RNA syntheses into the downstream genomic DNAs, could transcriptionally potentiate and preset chromatin structure of the cis-linked gene loci in oocytes and adult stem͞progenitor cells.

Long-range function of an intergenic retrotransposon

“…To determine if ERV-9 LTR was similarly expressed in Tg mice as in humans, we analyzed the transcription levels of ERV-9 LTR in various Tg mouse tissues. In humans, ERV-9 LTR is transcribed in the progenitor cells of erythroid and a number of other tissues and in oocytes and follicular granulosa cells (17). Similarly in Tg mice, ERV-9 LTR was transcribed at high levels in female germinal cells and erythroid and thymus progenitor cells (Fig.…”

“…An exception was mouse sperms, which expressed ERV-9 LTR at a high level (Fig. 5), in contrast to human sperms (17). The generally similar expression patterns of the ERV-9 LTR in Tg mice and humans indicated that mouse transgenics can serve as an appropriate system to test the function of primate ERV-9 LTRs.…”

“…In the β-globin gene locus, an ERV-9 LTR retrotransposon is stably integrated near the 5′ end of the locus control region (LCR), at 40-70 kb upstream of γ-and β-globin genes in higher primates from orangutans to humans (15). The ERV-9 LTRs in the human and chimpanzee globin gene loci, in reporter gene assays, exhibit prominent enhancer and promoter activities in embryonic and hematopoietic progenitor cells (14,15,17). To investigate whether this intergenic LTR retrotransposon serves a host function in regulating transcription of the far downstream globin genes, we generated transgenic (Tg) mice carrying the entire 100-kb human globin gene locus with or without the ERV-9 LTR.…”

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

“…Consistently, the ERV9-LTR shows germline-specific promoter activity even in zebrafish, as shown by a transgene where this LTR drives the expression of a green fluorescent protein reporter. 55 The mechanisms that lead to testis-specific expression appear to involve the transcription factors NF-Y and Sp1, 56 but may also be governed by the expression of antisense transcripts. 57 In any case, the virus appears to take advantage of ancient mechanisms for testicular transcription, to push the expression of its own genome, but also to re-assort this promoter activity with novel cellular genes.…”

Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements

“…Interspersed repeats have been suggested to function as cis-acting transcription regulators in some circumstances. For example, the mouse beta globin LCR was shown to express an intergenic transcript from an LTR-ERV9 promoter, which is responsible for local chromatin remodeling (Pi et al 2004). In addition, SINE repeats have been reported to contain DHS at the imprinted Igf2/H19 region and at the nonimprinted Sprr locus (Moore et al 1997;Martin et al 2004).…”