G-quadruplex DNA structures in human stem cells and differentiation

The establishment of cell identity during embryonic development involves the activation of specific gene expression programmes and is underpinned by epigenetic factors including DNA methylation and histone post-translational modifications. G-quadruplexes are four-stranded DNA secondary structures (G4s) that have been implicated in transcriptional regulation and cancer. Here, we show that G4s are key genomic structural features linked to cellular differentiation. We find that G4s are highly abundant in human embryonic stem cells and are lost during lineage specification. G4s are prevalent in enhancers and promoters. G4s that are found in common between embryonic and downstream lineages are tightly linked to transcriptional stabilisation of genes involved in essential cellular functions as well as transitions in the histone post-translational modification landscape. Furthermore, the application of small molecules that stabilise G4s causes a delay in stem cell differentiation, keeping cells in a more pluripotent-like state. Collectively, our data highlight G4s as important epigenetic features that are coupled to stem cell pluripotency and differentiation.

Automated summary

This study reveals that G-quadruplexes (G4s), four-stranded DNA secondary structures, are key genomic features linked to cellular differentiation. G4s are highly present in human embryonic stem cells but lost during lineage specification. They are mainly found in enhancers and promoters and are closely associated with transcriptional stabilization of genes involved in essential cellular functions and transitions in histone post-translational modification landscape. Moreover, stabilizing G4s with small molecules delays stem cell differentiation, maintaining a pluripotent-like state. These findings highlight the importance of G4s as epigenetic features coupled to stem cell pluripotency and differentiation.