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G-quadruplexes sense natural porphyrin metabolites for regulation of gene transcription and chromatin landscapes

ABSTRACT: G-quadruplexes (G4s) are unique noncanonical nucleic acid secondary structures, which could interact with transcription factors and chromatin remodelers to regulate cell type-specific transcriptome and shape chromatin landscapes. Based on the direct interactions between G4 and natural porphyrins, we established an in situ capture sequencing approach combining synthesized biotin-PEG4-Hemin and Cleavage Under Targets and Tagmentation (CUT&Tag) strategy to profile the Hemin binding sites in the human genome. We found that a proportion of G4s overlapped with Hemin binding sites and Hemin promoted genome-wide G4 formation at Hemin binding sites. Hemin treatments impaired gene transcription initiation and altered chromatin landscape with decreased H3K27ac and H3K4me3 modifications. Interestingly, G4 was not involved in the canonic Hemin-BACH1-NRF2-mediated enhancer activation process, highlighting an unprecedented G4-dependent mechanism for metabolic regulation of transcription. Furthermore, Hemin induced specific gene expression profiles in mouse primary hepatocytes, and block of Hemin degradation in mice by Hmox1 knockdown resulted in hepatic injury, providing in vivo insights for metabolic control of gene transcription by porphyrins.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE198658 | GEO | 2022/11/23

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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G-quadruplexes sense natural porphyrin metabolites for regulation of gene transcription and chromatin landscapes

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