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DNA G-quadruplex profiling in skeletal muscle stem cells reveals functional and mechanistic insights [CUT&RUN]

ABSTRACT: DNA G-quadruplexes (G4s) are non-canonical secondary structures formed in Guanine-rich DNA sequences and recent studies demonstrate G4s play important roles in modulating multiple biological processes through a variety of gene regulatory mechanisms. Emerging G4 profiling permit global mapping of endogenous G4 formation. Here in this study, we map the G4 landscapes in skeletal muscle stem cells (MuSCs) which are essential for injury induced muscle regeneration. Throughout the myogenic lineage progression of MuSCs from quiescent to activated to differentiated cells, we uncover dynamic endogenous G4 formation with a pronounced G4 induction when MuSCs become activated and proliferating. We further demonstrate that G4 induction promotes MuSC activation thus the regeneration process. Mechanistically, we found that promoter associated G4s regulate gene transcription in through facilitating DNA looping. Furthermore, we found that G4 sites are enriched for transcription factor (TF) binding events in activated MuSCs and MAX binds to G4 structures to promote E-P looping and gene transcription. The above uncovered global regulatory function/mechanism are further dissected on the paradigm of CCNE1 promoter demonstrating CCNE1 is a bona fid G4/MAX regulatory target in activated MuSCs. Altogether, our findings for the first time demonstrate the prevalent and dynamic formation of G4s in MuSCs and the mechanistic role of G4s in promoting gene expression and MuSC activation/proliferation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE289448 | GEO | 2025/08/20

REPOSITORIES: GEO

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Project description:DNA secondary structures are important for fundamental genome functions such as transcription and replication1. The G-quadruplex (G4) structural motif has been linked to gene regulation2,3 and genome instability4,5 and may be important to cancer development and other diseases6-8. Recently, ~700,000 discrete G4s have been observed in naked human single-stranded genomic DNA using G4-seq, a high-throughput sequencing technique that detects structural features in vitro.9 It is of vital importance to investigate G4 structures within an endogenous chromatin context, which until now remained elusive10,11. Herein, we address this via the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We identified ~10,000 endogenous G4 structures and show that G4s are predominantly seen in regulatory, nucleosome-depleted, chromatin regions. G4s were enriched in the promoters and 5âUTR regions of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Reorganization of the chromatin landscape using a histone deacetylase inhibitor, resulted in de novo G4 formation in new and more prominent regulatory, nucleosome-depleted regions associated with increased transcriptional output. Our findings suggest a striking relationship between promoter nucleosome-depleted regions, G4 formation and elevated transcriptional activity. Comparison between normal human epidermal keratinocytes and their immortalized counterparts revealed a ï¾7-fold greater G4 abundance in immortalized cells, of which 80 % were found in regulatory, nucleosome-depleted regions common to both cell types. Consequently, cells exhibiting more G4s displayed significantly increased transcriptional output and were more sensitive to growth inhibition by a small molecule G4 ligand. Overall, our results provide new mechanistic insights into where and when DNA adopts G4 structure in vivo. Our findings show for the first time that regulatory, nucleosome-depleted chromatin and transcriptional states predominantly shape the endogenous G4 DNA landscape. Two cell lines, treated with entinostat or untreated, analyzed to detect gene expression differences, presence of G-Qudruplexes and chromatin state. Each combination of conditions replicated in duplicates or triplicates.

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DNA G-quadruplex profiling in skeletal muscle stem cells reveals functional and mechanistic insights [CUT&RUN]

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