Abstract
Short Interspersed Nuclear Elements (SINEs) are non-autonomous retrotransposons that comprise a large fraction of the human genome. SINEs are demethylated in human disease, but whether SINEs become transcriptionally induced and how the resulting transcripts may affect the expression of protein coding genes is unknown. Here, we show that downregulation of the mRNA of the tumor suppressor gene BRCA1 is associated with increased transcription of SINEs and production of sense and antisense SINE small RNAs. We find that BRCA1 mRNA is post-transcriptionally down-regulated in a Dicer and Drosha dependent manner and that expression of a SINE inverted repeat with sequence identity to a BRCA1 intron is sufficient for downregulation of BRCA1 mRNA. These observations suggest that transcriptional activation of SINEs could contribute to a novel mechanism of RNA mediated post-transcriptional silencing of human genes.
Highlights
Transposable elements have been shown to affect gene regulation in plants and fungi [1] and in some animal species [2]
Retrotransposons known to be currently active in the human genome are long interspersed nuclear elements (LINEs), autonomous elements encoding their own enzymes needed for reverse transcription and genomic integration, and short interspersed nuclear elements (SINEs), non-autonomous elements that rely on the enzymes encoded within LINE sequences [5]
BRCA1 mRNA levels in MCF10A are comparable to the cancer cell lines (Figure 2), it is transcribed at a reduced rate in MCF10A cells compared to the fibroblast and cancer cell lines (Figure S2)
Summary
Transposable elements have been shown to affect gene regulation in plants and fungi [1] and in some animal species [2]. We found that BRCA1 downregulation in multiple breast cancer cell lines was not associated with promoter methylation or a reduced transcription rate, but instead correlated with increased bidirectional SINE transcription and the presence of SINE and BRCA1 small RNAs in cells. BRCA1 mRNA downregulation could be rescued by depleting Dicer and Drosha, and in non-cancer cells partial reduction in BRCA1 transcript levels could be achieved with ectopic transcription of double stranded SINE RNA with sequence identity to the BRCA1 transcript. From these results, we suggest a model in which high levels of SINE RNAs contribute to post-transcriptionally downregulate BRCA1 in human cells
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