G-quadruplexes regulate chromatin accessibility and gene expression in Bloom Syndrome [BlmSynFamily]

Bloom Syndrome (BS) is a recessive genetic disorder characterized by hyper-recombination and genome instability. It is caused by mutations in the conserved RecQ helicase gene, BLM, which is essential in maintaining genome integrity and unwinds various aberrant DNA structures. One such structure is DNA G-quadruplexes (G4s), which have broad regulatory functions. Although putative G4-forming sequences have been previously implicated in BS, it remains unclear what (dys)regulatory role, if any, endogenous G4 structures may play in BS. Here, we profiled chromatin accessibility and gene expression via ATAC-seq and RNA-seq and mapped endogenous G4 via ChIP-seq in wild-type (WT) vs. BS cell lines. We observed that in BS, differential G4 formation positively correlated with both chromatin accessibility and gene expression. Stabilizing G4 in WT cells with pyridostatin partially phenocopied BS. Additionally, data from a BS family showed that regions with increased chromatin accessibility in BS individuals were also enriched for G4-forming sequences. Our data showed that G4 formation is associated with higher chromatin accessibility and gene expression; likely in BS, unresolved G4 increases focal chromatin accessibility, thereby upregulating gene expression. In summary, our results revealed a central role of G4 in the molecular etiology of BS and provide a new perspective on BLM’s regulatory function through G4s.