Promoter expression of HERV-K (HML-2) provirus-derived sequences is related to LTR sequence variation and polymorphic transcription factor binding sites

Montesion, Meagan; Williams, Zachary H.; Subramanian, Ravi P.; Kuperwasser, Charlotte; Coffin, John M.

doi:10.1186/s12977-018-0441-2

Cited by 33 publications

(44 citation statements)

References 66 publications

(106 reference statements)

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“…Previously published reports demonstrate that transcription for both 3q12.3 and 4p16.1b is initiated in their respective 5′ LTRs, while the transcription for 22q11.23 is through a separate LTR, located a little over 500 bp upstream of the provirus [53]. Notably, it has been reported that the 5′ LTR from the provirus 3q12.3 has evolved to include a duplication of the HOX-PBX transcription binding site as well as a SNP in the RFX3 transcription factor binding site [54]. This may explain why this provirus is highly transcribed in many different cell types and why it no longer is able to function as a RcRE.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Gray

Jackson

et al. 2019

Retrovirology

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BackgroundThe HERV-K (HML-2) viruses are the youngest of the human endogenous retroviruses. They are present as several almost complete proviral copies and numerous fragments in the human genome. Many HERV-K proviruses express a regulatory protein Rec, which binds to an element present in HERV-K mRNAs called the RcRE. This interaction is necessary for the nucleo-cytoplasmic export and expression of HERV-K mRNAs that retain introns and plays a role analogous to that of Rev and the RRE in HIV replication. There are over 900 HERV-K RcREs distributed throughout the human genome. Thus, it was of interest to determine if Rev could functionally interact with selected RcRE elements that map either to HERV-K proviruses or human gene regions. This interaction would have the potential to alter the expression of both HERV-K mRNAs and cellular mRNAs during HIV-1 infection.ResultsIn this study we employed a combination of RNAseq, bioinformatics and cell-based functional assays. Potential RcREs were identified through a number of bioinformatic approaches. They were then tested for their ability to promote export and translation of a reporter mRNA with a retained intron in conjunction with Rev or Rec. Some of the selected elements functioned well with either Rev, Rec or both, whereas some showed little or no function. Rev function on individual RcREs varied and was also dependent on the Rev sequence. We also performed RNAseq on total and cytoplasmic RNA isolated from SupT1 cells expressing HIV Rev, with or without Tat, or HERV-K Rec. Proviral mRNA from three HERV-K loci (4p16.1b, 22q11.23 and most significantly 3q12.3) accumulated in the cytoplasm in the presence of Rev or Tat and Rev, but not Rec. Consistent with this, the 3′ RcRE from 3q12.3 functioned well with HIV-Rev in our reporter assay. In contrast, this RcRE showed little or no function with Rec.ConclusionsThe HIV Rev protein can functionally interact with many RcREs present in the human genome, depending on the RcRE sequence, as well as the Rev sequence. This leads to export of some of the HERV-K proviral mRNAs and also has the potential to change the expression of non-viral genes.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Gray

Jackson

et al. 2019

Retrovirology

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show abstract

“…Previously published reports demonstrate that transcription for both 3q12.3 and 4p16.1b is initiated in their respective 5' LTRs, while the transcription for 22q11.23 is through a separate LTR, located a little over 500bp upstream of the provirus (53). Notably, it has been reported that the 5' LTR from the provirus 3q12.3 has evolved to include a duplication of the HOX-PBX transcription binding site as well as a SNP in the RFX3 transcription factor binding site (54). This may explain why this provirus is highly transcribed in many different cell types and why it no longer is able to function as a RcRE.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Gray¹,

Jackson²,

Jackson³

et al. 2019

Preprint

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BackgroundThe HERV-K (HML-2) viruses are the youngest of the human endogenous retroviruses. They are present as several almost complete proviral copies and numerous fragments in the human genome. Many HERV-K proviruses express a regulatory protein Rec, which binds to an element present in HERV-K mRNAs called the RcRE. This interaction is necessary for the nucleo-cytoplasmic export and expression of HERV-K mRNAs that retain introns and plays a role analogous to that of Rev and the RRE in HIV replication. There are over 900 HERV-K RcREs distributed throughout the human genome. Thus, it was of interest to determine if Rev could functionally interact with selected RcRE elements that map either to HERV-K proviruses or human gene regions. This interaction would have the potential to alter the expression of both HERV-K mRNAs and cellular mRNAs during HIV-1 infection. ResultsIn this study we employed a combination of RNAseq, bioinformatics and cell-based functional assays. Potential RcREs were identified through a number of bioinformatic approaches. They were then tested for their ability to promote export and translation of a reporter mRNA with a retained intron in conjunction with Rev or Rec. Some of the selected elements functioned well with either Rev, Rec or both, whereas some showed little or no function. Rev function on individual RcREs varied and was also dependent on the Rev sequence. We also performed RNAseq on total and cytoplasmic RNA isolated from SupT1 cells expressing HIV Rev, with or without Tat, or HERV-K Rec. Proviral mRNA from three HERV-K loci (4p16.1b, 22q11.23 and most significantly 3q12.3) accumulated in the cytoplasm in the presence of Rev or Tat and Rev, but not Rec. Consistent with this, the 3' RcRE from 3q12.3 functioned well with HIV-Rev in our reporter assay. In contrast, this RcRE showed little or no function with Rec. ConclusionsThe HIV Rev protein can functionally interact with many RcREs present in the human genome, depending on the RcRE sequence, as well as the Rev sequence. This leads to export of some of the HERV-K proviral mRNAs and also has the potential to change the expression of non-viral genes.

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“…An in vitro model of human mammary epithelial cell transformation indicated the 5 LTR promoter activity is active in tumorigenic cells only, suggesting that the cellular environment of a cancer cell is a critical component for induction of LTR promoter activity (Montesion et al, 2017). LTR sequence variations, causing transcription factor binding site polymorphisms, are positively correlated with promoter expression patterns in human breast cancer cell lines (Montesion et al, 2018; Figure 2G). The presence of interferon-stimulated response elements (ISREs) in the promoter region of HERV-K suggests its expression could be regulated by inflammatory cytokines, which could explain its implication in autoimmune disorders (Manghera et al, 2016; Figure 2H).…”

Section: Long Terminal Repeats (Ltrs)mentioning

confidence: 99%

Human Endogenous Retrovirus K (HML-2) in Health and Disease

2020

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Human endogenous retroviruses (HERVs) are derived from exogenous retrovirus infections in the evolution of primates and account for about 8% of the human genome. They were considered as silent passengers within our genomes for a long time, however, reactivation of HERVs has been associated with tumors and autoimmune diseases, especially the HERV-K (HML-2) family, the most recent integration groups with the least number of mutations and the most biologically active to encode functional retroviral proteins and produce retrovirus-like particles. Increasing studies are committed to determining the potential role of HERV-K (HML-2) in pathogenicity. Although there is still no evidence for HERV-K (HML-2) as a direct cause of diseases, aberrant expression profiles of the HERV-K (HML-2) transcripts and their regulatory function to their proximal host-genes were identified in different diseases. In this review, we summarized the advances between HERV-K (HML-2) and diseases to provide basis for further studies on the causal relationship between HERV-K (HML-2) and diseases. We recommended more attention to polymorphic integrated HERV-K (HML-2) loci which could be genetic causative factors and be associated with inter-individual differences in tumorigenesis and autoimmune diseases.

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Promoter expression of HERV-K (HML-2) provirus-derived sequences is related to LTR sequence variation and polymorphic transcription factor binding sites

Cited by 33 publications

References 66 publications

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Human Endogenous Retrovirus K (HML-2) in Health and Disease

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