G-quadruplex DNA structures in human stem cells and differentiation

Katherine G. Zyner, Angela Simeone, Sean M. Flynn, Colm Doyle, Giovanni Marsico, Santosh Adhikari, Guillem Portella, David Tannahill and Shankar Balasubramanian ()
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Katherine G. Zyner: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way
Angela Simeone: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way
Sean M. Flynn: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way
Colm Doyle: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way
Giovanni Marsico: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way
Santosh Adhikari: University of Cambridge, Lensfield Road
Guillem Portella: University of Cambridge, Lensfield Road
David Tannahill: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way
Shankar Balasubramanian: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-021-27719-1

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