Abstract
BackgroundCertain post-translational modifications to histones, including H3K4me3, as well as binding sites for the transcription factor STAT1, predict the site of integration of exogenous gamma-retroviruses with great accuracy and cell-type specificity. Statistical methods that were used to identify chromatin features that predict exogenous gamma-retrovirus integration site selection were exploited here to determine whether cell type-specific chromatin markers are enriched in the vicinity of endogenous retroviruses (ERVs).ResultsAmong retro-elements in the human genome, the gamma-retrovirus HERV-H was highly associated with H3K4me3, though this association was only observed in embryonic stem (ES) cells (p < 10-300) and, to a lesser extent, in induced pluripotent stem (iPS) cells. No significant association was observed in nearly 40 differentiated cell types, nor was any association observed with other retro-elements. Similar strong association was observed between HERV-H and the binding sites within ES cells for the pluripotency transcription factors NANOG, OCT4, and SOX2. NANOG binding sites were located within the HERV-H 5′LTR itself. OCT4 and SOX2 binding sites were within 1 kB and 2 kB of the 5′LTR, respectively. In keeping with these observations, HERV-H RNA constituted 2% of all poly A RNA in ES cells. As ES cells progressed down a differentiation pathway, the levels of HERV-H RNA decreased progressively. RNA-Seq datasets showed HERV-H transcripts to be over 5 kB in length and to have the structure 5′LTR-gag-pro-3′LTR, with no evidence of splicing and no intact open reading frames.ConclusionThe developmental regulation of HERV-H expression, the association of HERV-H with binding sites for pluripotency transcription factors, and the extremely high levels of HERV-H RNA in human ES cells suggest that HERV-H contributes to pluripotency in human cells. Proximity of HERV-H to binding sites for pluripotency transcription factors within ES cells might be due to retention of the same chromatin features that determined the site of integration of the ancestral, exogenous, gamma-retrovirus that gave rise to HERV-H in the distant past. Retention of these markers, or, alternatively, recruitment of them to the site of the established provirus, may have acted post-integration to fix the provirus within the germ-line of the host species. Either way, HERV-H RNA provides a specific marker for pluripotency in human cells.
Highlights
Certain post-translational modifications to histones, including H3K4me3, as well as binding sites for the transcription factor STAT1, predict the site of integration of exogenous gamma-retroviruses with great accuracy and cell-type specificity
Among all Long terminal repeat (LTR), only Human endogenous retrovirus (HERV)-H showed a significant association with H3K4me3, though this association was only with some human cell types; the location of the endogenous gamma-retrovirus was associated with H3K4me3 profiles in embryonic stem (ES) cells (F-score >0.8; p < 10-300, by Fisher exact test) and, to a lesser extent, in induced pluripotent stem (iPS) cells (F-score >0.7; p < 10-100)
It is noteworthy that the adjacent HERV-L is not expressed, even if it is Discussion This study discovered a strong association between the genomic location of HERV-H proviruses and H3K4me3modified histones, that is exclusive to human ES and some iPS cells
Summary
Certain post-translational modifications to histones, including H3K4me, as well as binding sites for the transcription factor STAT1, predict the site of integration of exogenous gamma-retroviruses with great accuracy and cell-type specificity. Statistical methods that were used to identify chromatin features that predict exogenous gamma-retrovirus integration site selection were exploited here to determine whether cell type-specific chromatin markers are enriched in the vicinity of endogenous retroviruses (ERVs). Vertebrate genomes contain retroviral sequences that are believed to be remnants of exogenous retroviral infection from the distant past [1]. The genesis of these endogenous retroviruses (ERVs) necessitates establishment of provirus. HERVs can be activated by exogenous retrovirus infection [15] and, in reciprocal fashion, the immune response to these elements can influence the outcome of infection by pathogenic, exogenous retroviruses such as HIV-1 [16,17]
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