GQ-DNABERT reveals GQ proximal enhancer–promoter interactions associated with tissue-specific transcription

Alternative DNA conformation formed by sequences called flipons are thought to play an important role in regulating various genomic processes, either repressing or enhancing transcription, chromatin organization, DNA repair, telomere maintenance, RNA splicing, translation, and stress responses. The formation of G-quadruplexes (GQs) has been investigated experimentally using various methodologies with varying degrees of overlap between the results underscoring the need for a gold-standard GQ dataset. With this aim we trained a large language model, GQ-DNABERT using EndoQuad, the most comprehensive human GQ dataset. GQ-DNABERT recalled the training data and predicted de novo GQs in intergenic and intronic regions, enriched for cis-regulatory elements (cCREs) and ATAC-seq peaks. We evaluated the predicted GQ-DNABERT proximal enhancer-promoter (pEP) pairs, using annotations from ENdb, ENCODE, Zoonomia, Chromium multiomics scATAC-seq and scRNA-seq data from normal cells, and cCREs from normal-cancer pairs. We found GQ pEP pairs correlating with gene expression, with some pairings potentially acting as tissue-specific switches. Genes with GQ pEP pairs in cancer cells are enriched in different processes compared to the corresponding normal tissues. Overall, GQ-DNABERT is a valuable tool for extending and harmonizing data collected ex vivo. We demonstrate the usefulness of GQ-DNABERT for investigating transcriptional regulation in single-cell experiments.