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Genome-wide analysis of 8-oxoguanine DNA glycosylase-1

ABSTRACT: We report the application of ChIP-Sequencing for profiling genome-wide distribution of 8-oxoguanine DNA glycosylase (OGG1) which is a DNA base excision repair protein, after TNF exposure of cells. By obtaining an average of over 18 million of total reads per sample and over 19.5 million of unique reads per sample from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of HEK293 cells. We performed gene ontology and functional pathway analysis of genes associate with peaks, and identify regions of the genomes (e.g. promoter, introns, etc) where the peaks tend to occur. The results show that OGG1 is primarily associated with promoter regions in vicinity of transcription factor binding sites 5' of transcription start sites (TSS). This pattern of distribution occurs in spite of genome-wide oxidative modifications of guanine (primarily 8-oxoG). OGG1 increased highly significant (1e-09 to 1e-517) enrichment of 57 transcription factor binding sites including those for Sox(2, 3, 6, 10), RUNX, RUNX(1, 2), HOX(C, D), STAT(1, 3, 6), IRF(1 to 4), NF-κB. In controls, the DNA was chromatin immunoprecipitated using antibody to NF-κB/RelA. These and other data derived from further analysis, suggest that OGG1 modulates binding of transcription factors and gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75562 | GEO | 2018/07/15

REPOSITORIES: GEO

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Project description:Runx1 and Runx3 function redundantly in early T-development, and together drive T-lineage developmental progression by regulating distinct sets of genes in different stages. Context-specific Runx target genes are particularly enriched near Runx binding sites that dynamically shift from pre-T-commitment stages (Phase 1) to post-T-commitment stages (Phase 2). As total Runx activities (Runx1+Runx3) are maintained stably throughout early T-development stages, yet Runx factors physically interact with multiple collaborators, we hypothesized that different Runx-collaborating transcription factors compete to recruit a limited pool of Runx transcription factors. To test whether increasing Runx availability can alter Runx DNA-binding site choices, Runx1 overexpression vectors were introduced to two different systems. First, we increased Runx1 expression in a DN3-like cell line (representing a post-commitment, Phase 2 stage) in the presence or absence of exogenous Phase 1 co-factor, PU.1. Second, we increased Runx1 expression in Phase 1 primary cells which naturally express PU.1 and other Phase 1 collaborators. Then, Runx1 binding behaviors were measured using ChIP-seq or CUT&RUN (C&R). A modest increase of Runx1 levels (about 2-3 fold increase) substantially increased the number of Runx binding sites seen and the intensity of occupancy in both systems. When Runx expression was at physiological levels, PU.1 dominated Runx1 site choice before T commitment by recruiting Runx1 to PU.1 sites. The Phase 2 cell line system showed that it did this while depleting Runx1 from alternative high quality Runx motif sites. However, when Runx1 was overexpressed, Runx1 was still recruited to PU.1 sites, but this recruitment did not evacuate Runx1 occupancy from default preferred sites. Notably, Runx1 overexpression in primary Phase 1 cells caused precocious occupancy of post-commitment, Phase 2-specific sites. We found that these are often co-occupied with TCF1, E2A, and HEB, but have minimal co-binding with PU.1. In addition, Runx1 overexpression resulted in new binding sites that were not normally observed in pro-T cells, which are mostly sequestered by closed chromatin normally although they harbor more numerous Runx motifs. Thus, these data suggest that Runx DNA binding site choices are sensitive to Runx concentration and co-factors during early T-development.

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Genome-wide analysis of 8-oxoguanine DNA glycosylase-1

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