Background: Putative G-quadruplex-forming sequences (PQS) have long been implicated in regulation of transcription, though the actual mechanisms are not well understood. One proposed mechanism involves the activity of PQS-specific helicases belonging to the RecQ helicase family. However, patterns of PQS that correlate with transcriptional sensitivity to RecQ helicases are not well studied, and no adequate transcriptional model exists to account for PQS effects. Methods: To better understand PQS transcriptional effects, we analyze PQS motifs in genes differentially-transcribed in Bloom Syndrome (BS) and Werner Syndrome (WS), two disorders resulting in loss of PQS-interacting RecQ helicases. We also correlate PQS genome-wide with transcription in multiple human cells lines while controlling for epigenetic status. Finally, we perform neural network clustering of PQS motifs to assess whether certain motifs are over-represented in genes sensitive to RecQ helicase loss. Results: By analyzing PQS motifs in promoters of genes differentially-transcribed in BS and WS, we demonstrate that abundance of promoter PQS is generally higher in down-regulated genes and lower in up-regulated genes, and show that these effects are position-dependent. To interpret these correlations we determined genome-wide PQS correlations with transcription while controlling for epigenetic status. Our results identify multiple discrete transcription start site-proximal positions where PQS are correlated with either increased or decreased transcription. Finally, we report neural network clustering analysis of PQS motifs demonstrating that genes differentially-expressed in BS and WS are significantly biased in PQS motif composition. Conclusions: Our findings unveil unappreciated detail in the relationship between PQS, RecQ helicases, and transcription. We show that promoter PQS are generally correlated with reduced gene expression, and that this effect is relieved by RecQ helicases. We also show that PQS at certain positions on the downstream sense strand are correlated with increased transcription. We therefore propose a new transcriptional model in which promoter PQS have at least two distinct types of transcriptional regulatory effects.
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