G-quadruplex DNA structures in human stem cells and differentiation

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.

Epigenomic Features and Potential Functions of K+ and Na+ Favorable DNA G-Quadruplexes in Rice

“…It has been reported that DNA G4s play regulatory roles in modulating the expression of certain genes, thereby being involved in various biological processes [ 15 , 17 , 18 , 19 , 20 , 21 , 22 ]. They include, but are not limited to, DNA replication [ 10 , 23 ], immunoglobulin switch recombination [ 24 ], telomere maintenance [ 10 , 11 ], genome instability [ 10 , 25 ], gene transcription [ 6 , 15 , 26 , 27 , 28 ], reprogramming of DNA or chromatin modifications [ 29 , 30 ], human stem cell differentiation [ 31 ], and human diseases [ 32 , 33 ]. In particular, they can be considered as potential drug targets for human disease treatment [ 11 , 25 , 34 , 35 ], which attracts more attention and boosts G4 studies in pharmacogenomics.…”

Putative G-quadruplex Formation in the Upstream Region of mTOR Gene

“…These studies further highlight the potential tunability of mTOR expression via the secondary structure of P2 G4. As evidenced by the recent discoveries of novel G-quadruplexes 60,65,66,67,68,69 , this unique secondary structure provides an opportunity for the future design and synthesis of mTOR specific ligands. This study would also assist in identifying diverse targets for alternative therapeutic approaches to control overexpression of mTOR gene paving the path for detailed studies in this frontier.…”

Ligands stimulating antitumour immunity as the next G-quadruplex challenge

“…Human embryonic stem cells (hESC) show higher G4 levels than differentiated cells, and their homeostatic maintenance may be an important chromatin feature for transcriptional control and cell fate specification [ 36 ]. Notably, the authors found that G4 stabilization mediated by PhenDC3 at not cytotoxic concentration causes delayed differentiation of hESC due to failure of pluripotency exit [ 36 ]. The results thus emphasize a role of G4 structures in epigenetic regulation of gene expression and cellular differentiation.…”