G-quadruplex DNA structures in human stem cells and differentiation

• Published in: Nature communications Vol. 13; no. 1; p. 142
• Main Authors: Zyner, Katherine G., Simeone, Angela, Flynn, Sean M., Doyle, Colm, Marsico, Giovanni, Adhikari, Santosh, Portella, Guillem, Tannahill, David, Balasubramanian, Shankar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-01-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/100; 13/31; 14/19; 45/15; 45/77; 45/88; 45/91; 631/136/532; 631/337/176; 631/337/2019; 631/92/147; Biomarkers - metabolism; Cell Differentiation; Cell Line; Cell Lineage - genetics; Cell self-renewal; Cellular structure; Deoxyribonucleic acid; Differentiation (biology); DNA; DNA - genetics; DNA - metabolism; DNA Methylation; Embryo cells; Embryogenesis; Embryonic growth stage; Enhancer Elements, Genetic; Enhancers; Epigenesis, Genetic; Epigenetics; G-Quadruplexes; Gene Expression; Gene regulation; Histones; Histones - genetics; Histones - metabolism; Human Embryonic Stem Cells - cytology; Human Embryonic Stem Cells - metabolism; Humanities and Social Sciences; Humans; multidisciplinary; Nanog Homeobox Protein - genetics; Nanog Homeobox Protein - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nestin - genetics; Nestin - metabolism; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; PAX6 Transcription Factor - genetics; PAX6 Transcription Factor - metabolism; Pluripotency; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Post-translation; Promoter Regions, Genetic; Protein Processing, Post-Translational; Receptors, Nerve Growth Factor - genetics; Receptors, Nerve Growth Factor - metabolism; Science; Science (multidisciplinary); Stem cells; Transcription; Transcription Factor AP-2 - genetics; Transcription Factor AP-2 - metabolism; Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27719-1

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.
Whether G-quadruplexes (G4s) regulate stem cell self-renewal and fate determination during embryonic development is not well understood. Here, the authors reveal that the embryonic stem cell state is defined by very high G4 abundance. G4s are progressively lost during differentiation as cells transit to lower lineage potential while artificial G4 stabilisation leads to delayed differentiation.