Abstract
Internal RNA modifications have been known for decades, however their roles in mRNA regulation have only recently started to be elucidated. Here we investigated the most abundant mRNA modification, N6-methyladenosine (m6A) in transcripts from the hippocampus of HIV transgenic (Tg) rats. The distribution of m6A peaks within HIV transcripts in HIV Tg rats largely corresponded to the ones observed for HIV transcripts in cell lines and T cells. Host transcripts were found to be differentially m6A methylated in HIV Tg rats. The functional roles of the differentially m6A methylated pathways in HIV Tg rats is consistent with a key role of RNA methylation in the regulation of the brain transcriptome in chronic HIV disease. In particular, host transcripts show significant differential m6A methylation of genes involved in several pathways related to neural function, suggestive of synaptodendritic injury and neurodegeneration, inflammation and immune response, as well as RNA processing and metabolism, such as splicing. Changes in m6A methylation were usually positively correlated with differential expression, while differential m6A methylation of pathways involved in RNA processing were more likely to be negatively correlated with gene expression changes. Thus, sets of differentially m6A methylated, functionally-related transcripts appear to be involved in coordinated transcriptional responses in the context of chronic HIV. Altogether, our results support that m6A methylation represents an additional layer of regulation of HIV and host gene expression in vivo that contributes significantly to the transcriptional effects of chronic HIV.
Highlights
An extensive repertoire of modifications is believed to contribute to the regulation of RNA processing, metabolism and expression
The modification identified is N6methyladenosine (m6A) methylation in HIV transcripts in the hippocampus of HIV Tg rats showed enrichment in the 5’ and 3’ of the provirus most prominently corresponding to the 5’ and 3’ untranslated regions (UTRs) and long-terminal repeat (LTR) and the nef open reading frame (ORF), which partially overlaps with the 3’ LTR (Fig 2B)
We found that both HIV and host transcripts of HIV Tg rats contain m6A methylation
Summary
An extensive repertoire of modifications is believed to contribute to the regulation of RNA processing, metabolism and expression. It has long been known that transfer RNA (tRNA), ribosomal RNA (rRNA) and both mRNA and noncoding RNA (ncRNA) contain multiple modifications [1,2,3,4,5]. 7-methylguanosine cap that is added at the 5’ end of all cellular mRNAs, several internal RNA modifications have been described, which include N6-methyladenosine (m6A), 2’-O-methyladenosine (Am), N6-2’-O-methyladenosine (m6Am), pseudouridine, and 5-methylcytosine, among others [6,7,8,9,10]. By far the most abundant RNA modification identified is N6methyladenosine (m6A) [1, 2]. MRNAs are modified by m6A preferentially in the 30 untranslated regions (UTRs), near the stop codons within mRNAs and within long internal exons, and m6A modification appears to be conserved between humans and rodents [1] While m6A has been found in mRNAs from diverse tissue types, the brain has especially high levels of m6A [13]. mRNAs are modified by m6A preferentially in the 30 untranslated regions (UTRs), near the stop codons within mRNAs and within long internal exons, and m6A modification appears to be conserved between humans and rodents [1]
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