Genome-wide formation of G-quadruplex DNA structures originating from Long Interspersed Elements in Alzheimer’s disease neurons
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE133113 | GEO | 2021/01/20
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.
2016-08-05 | E-GEOD-76688 | biostudies-arrayexpress
Project description:G-quadruplex structures (G4s) have been identified in genomes of multiple organisms and proven to play important epigenetic regulatory roles in various cellular functions. However, the G4 formation mechanism remains largely unknown. Here, we found a negative correlation between DNA 5mC methylation and G4 abundance. The abundance of genomic G4s significantly increased when the whole-genome methylation level was reduced in DNMT1-knockout cells. This increase was then suppressed by DNMT1 over-expression. And more G4s were detected in the hypomethylated cancer cell line HepG2 and rectal cancer tissues. Besides, 5mC modification significantly inhibited G4 formation of the potential G-quadruplex sequences (PQSs). The transcription of genes with 5mC modification sites in their promoter PQSs was affected after treatment with G4 stabilizer pyridostatin or methylation inhibitor 5-aza-dC. The global reduction of genomic methylation elevates gene transcription levels through increased G4s. Taken together, DNA 5mC methylation prevents PQSs from folding into G4s in genomes.
2024-06-20 | GSE270034 | GEO
Project description:G-quadruplex (G4) structural motifs have been linked to transcription, replication and genome instability and are implicated in cancer and other diseases. However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context. Herein we address this through the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5' UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor-induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.
2016-08-05 | GSE76688 | GEO
Project description:G-quadruplex structures (G4s) have been identified in genomes of multiple organisms and proven to play important epigenetic regulatory roles in various cellular functions. However, the G4 formation mechanism remains largely unknown. Here, we found a negative correlation between DNA 5mC methylation and G4 abundance. The abundance of genomic G4s significantly increased when the whole-genome methylation level was reduced in DNMT1-knockout cells. This increase was then suppressed by DNMT1 over-expression. And more G4s were detected in the hypomethylated cancer cell line HepG2 and rectal cancer tissues. Besides, 5mC modification significantly inhibited G4 formation of the potential G-quadruplex sequences (PQSs). The transcription of genes with 5mC modification sites in their promoter PQSs was affected after treatment with G4 stabilizer pyridostatin or methylation inhibitor 5-aza-dC. The global reduction of genomic methylation elevates gene transcription levels through increased G4s. Taken together, DNA 5mC methylation prevents PQSs from folding into G4s in genomes.
2024-06-20 | GSE270035 | GEO
Project description:G-quadruplex structures (G4s) have been identified in genomes of multiple organisms and proven to play important epigenetic regulatory roles in various cellular functions. However, the G4 formation mechanism remains largely unknown. Here, we found a negative correlation between DNA 5mC methylation and G4 abundance. The abundance of genomic G4s significantly increased when the whole-genome methylation level was reduced in DNMT1-knockout cells. This increase was then suppressed by DNMT1 over-expression. And more G4s were detected in the hypomethylated cancer cell line HepG2 and rectal cancer tissues. Besides, 5mC modification significantly inhibited G4 formation of the potential G-quadruplex sequences (PQSs). The transcription of genes with 5mC modification sites in their promoter PQSs was affected after treatment with G4 stabilizer pyridostatin or methylation inhibitor 5-aza-dC. The global reduction of genomic methylation elevates gene transcription levels through increased G4s. Taken together, DNA 5mC methylation prevents PQSs from folding into G4s in genomes.
2024-06-20 | GSE270033 | GEO
Project description:G-quadruplex structures (G4s) have been identified in genomes of multiple organisms and proven to play important epigenetic regulatory roles in various cellular functions. However, the G4 formation mechanism remains largely unknown. Here, we found a negative correlation between DNA 5mC methylation and G4 abundance. The abundance of genomic G4s significantly increased when the whole-genome methylation level was reduced in DNMT1-knockout cells. This increase was then suppressed by DNMT1 over-expression. And more G4s were detected in the hypomethylated cancer cell line HepG2 and rectal cancer tissues. Besides, 5mC modification significantly inhibited G4 formation of the potential G-quadruplex sequences (PQSs). The transcription of genes with 5mC modification sites in their promoter PQSs was affected after treatment with G4 stabilizer pyridostatin or methylation inhibitor 5-aza-dC. The global reduction of genomic methylation elevates gene transcription levels through increased G4s. Taken together, DNA 5mC methylation prevents PQSs from folding into G4s in genomes.
2022-12-20 | GSE221436 | GEO
Project description:G-quadruplex structures (G4s) have been identified in genomes of multiple organisms and proven to play important epigenetic regulatory roles in various cellular functions. However, the G4 formation mechanism remains largely unknown. Here, we found a negative correlation between DNA 5mC methylation and G4 abundance. The abundance of genomic G4s significantly increased when the whole-genome methylation level was reduced in DNMT1-knockout cells. This increase was then suppressed by DNMT1 over-expression. And more G4s were detected in the hypomethylated cancer cell line HepG2 and rectal cancer tissues. Besides, 5mC modification significantly inhibited G4 formation of the potential G-quadruplex sequences (PQSs). The transcription of genes with 5mC modification sites in their promoter PQSs was affected after treatment with G4 stabilizer pyridostatin or methylation inhibitor 5-aza-dC. The global reduction of genomic methylation elevates gene transcription levels through increased G4s. Taken together, DNA 5mC methylation prevents PQSs from folding into G4s in genomes.
2022-12-20 | GSE221435 | GEO
Project description:Control of DNA methylation level is critical for gene regulation, and the factors that govern hypomethylation at CpG islands (CGIs) are still being uncovered. Here, we provide evidence that G-quadruplex (G4) DNA secondary structures are genomic features that influence methylation at CGIs. We show that the presence of G4 structure is tightly associated with CGI hypomethylation. Surprisingly, we find that these G4 sites are enriched for DNA methyltransferase 1 (DNMT1) occupancy, which is consistent with our biophysical observations that DNMT1 exhibits higher binding affinity for G4s as compared to duplex, hemi-methylated or single-stranded DNA. The biochemical assays also show that the G4 structure itself, rather than sequence, inhibits DNMT1 enzymatic activity. Based on these data, we propose that G4 formation sequesters DNMT1 thereby protecting certain CGIs from methylation and inhibiting local methylation.
2018-07-16 | GSE107690 | GEO
Project description:Genome-wide formation of G-quadruplex DNA structures originating from Long Interspersed Elements in Alzheimer’s disease neurons
| PRJNA549960 | ENA
Project description:Single-stranded genomic DNA can fold into G-quadruplex (G4) structures or form DNA:RNA hybrids (R loops). Recent evidence suggests that such non-canonical DNA structures affect gene expression, DNA methylation, replication fork progression and genome stability. When and how G4 structures form and are resolved remains unclear. Here we report the use of Cleavage Under Targets and Tagmentation (CUT&Tag) for mapping native G4 in mammalian cell lines at high resolution and low background. Mild native conditions used for the procedure retain more G4 structures and provide a higher signal-to-noise ratio than ChIP-based methods. We determine the G4 landscape of mouse embryonic stem cells (mESC), discovering G4 formation at active and poised promoters and enhancers. We discover that the presence of G4 motifs and G4 structures distinguishes active and primed enhancers in mESCs. Further performing R-loop CUT&Tag, we demonstrate the widespread co-occurence of single-stranded DNA, G4s and R loops, suggesting an intricate interrelation of non-canonical DNA structures, transcription and the formation and turnover of G4s.
2021-04-27 | GSE173103 | GEO