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Distinct p53 Genomic Binding Patterns in Normal and Cancer-derived Human Cells

ABSTRACT: We report here genome-wide analysis of the tumor suppressor p53 binding sites in normal human cells. 743 high-confidence ChIP-seq peaks representing putative genomic binding sites were identified in normal IMR90 fibroblasts using a reference chromatin sample. More than 40 % were located within 2 kb of a transcription start site (TSS), a distribution similar to that documented for individually studied functional p53 binding sites and to date not observed by previous genome-wide studies. Nearly half of the high-confidence binding sites in the IMR90 cells reside in CpG islands, in marked contrast to sites reported in cancer-derived cells. The distinct genomic features of the IMR90 binding sites do not reflect a distinct preference for specific sequences, since the de novo developed p53 motif based on our study is similar to those reported by genome-wide studies of cancer cells. More likely the different chromatin landscape in normal compared to cancer-derived cells influences p53 binding via modulating availability of the sites. We compared the IMR90 ChIP-seq peaks to the recently published IMR90 methylome1, and demonstrated that they are enriched at hypomethylated DNA. Our study represents the first genome-wide, de novo mapping of p53 binding sites in normal human cells and reveals that p53 binding sites reside in distinct genomic landscapes in normal and cancer-derived human cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE31558 | GEO | 2011/12/08

SECONDARY ACCESSION(S): PRJNA145681

REPOSITORIES: GEO

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Distinct p53 Genomic Binding Patterns in Normal and Cancer-derived Human Cells

Project description:We report here genome-wide analysis of the tumor suppressor p53 binding sites in normal human cells. 743 high-confidence ChIP-seq peaks representing putative genomic binding sites were identified in normal IMR90 fibroblasts using a reference chromatin sample. More than 40 % were located within 2 kb of a transcription start site (TSS), a distribution similar to that documented for individually studied functional p53 binding sites and to date not observed by previous genome-wide studies. Nearly half of the high-confidence binding sites in the IMR90 cells reside in CpG islands, in marked contrast to sites reported in cancer-derived cells. The distinct genomic features of the IMR90 binding sites do not reflect a distinct preference for specific sequences, since the de novo developed p53 motif based on our study is similar to those reported by genome-wide studies of cancer cells. More likely the different chromatin landscape in normal compared to cancer-derived cells influences p53 binding via modulating availability of the sites. We compared the IMR90 ChIP-seq peaks to the recently published IMR90 methylome1, and demonstrated that they are enriched at hypomethylated DNA. Our study represents the first genome-wide, de novo mapping of p53 binding sites in normal human cells and reveals that p53 binding sites reside in distinct genomic landscapes in normal and cancer-derived human cells. Identification of genomic p53 binding sites in normal human cells by ChIP-seq.

2011-12-08 | E-GEOD-31558 | biostudies-arrayexpress

Cell Context Dependent p53 Genome-Wide Binding Patterns and Enrichment at Repeats

Project description:We mapped the genomic binding sites of the tumor suppressor protein p53 in the human colorectal cancer cell line HCT116 and report here that the binding patterns of endogenous wild type p53 differed significantly between the genomes of the cancer cell line HCT116 and the normal human IMR90 fibroblasts (GSE31558) under the same experimental conditions (6 hr treatment with 5-fluorouracil). p53 binding differences affect promoter regions, CpG islands and major families of human repeat elements such as LTR, LINE and SINE. While p53 genomic binding sites residing in repeats have been reported before, we show here that the fraction of the p53 genomic binding sites residing in different repeat families differs between the normal and cancer human cell lines. We confirm that the p53 genomic binding sites in HCT116 cells are excluded from CpG islands, an observation we made previously based on analysis of data reported by others. While the p53 ability to elicit stress-specific and cell-type-specific responses is well documented, how this specificity is established, at the level of binding to the genome and/or during post-binding events, represents an open question. Our data indicate that p53 binding to the human genome is cell line-specific and highly selective. The differences in the p53 genome-wide binding patterns between the cancer cell line HCT116 and the normal cell line IMR90, namely exclusion from CpG islands and enrichment at repeats in HCT116, likely reflect cancer-associated epigenetic changes in the chromatin. Identification of genomic p53 binding sites in HCT116 cells by ChIP-seq.

2014-11-21 | E-GEOD-58714 | biostudies-arrayexpress

Cell Context Dependent p53 Genome-Wide Binding Patterns and Enrichment at Repeats

2014-11-21 | GSE58714 | GEO

Homo sapiens

Project description:Genome wide maps of p53 binding in IMR90 cells

| PRJNA182950 | ENA

Homo sapiens

Project description:Chromatin dynamics of p53 binding sites in IMR90

| PRJNA253315 | ENA

Mutant telomerase RNAs induce DNA damage and apoptosis via the TRF2-ATM pathway in telomerase-overexpressing primary fibroblasts

Project description:Mutant template human telomerase RNAs (MT-hTers) have been shown to induce apoptosis in various cancer cells with high telomerase activity. However, the mechanism by which MT-hTers inhibit growth of cancer cells and their effects on normal cells remain unknown. To determine the effects of MT-hTers on normal cells, MT-hTer-47A and -AU5 were introduced into IMR90 lung fibroblasts that have low telomerase levels. Growth of IMR90 cells following MT-hTers infection was not significantly impaired; however, similar treatments in telomerase-overexpressing IMR90 (IMR90 WThTERT) cells inhibited cell proliferation and induced apoptosis. Confocal microscopy showed that MT-hTers induced DNA damage foci i.e. 53BP1 and γ-H2AX in IMR90 WThTERT cells. Microarray analysis revealed that GADD45γ was significantly elevated in MT-hTers treated IMR90 WThTERT cells. MT-hTers also induced ATM phosphorylation at Ser 1981 in IMR90 WThTERT cells, and Western blot analysis revealed high levels of phosphorylated p53 following down-regulation of cellular TRF2 expression in MT-hTers treated IMR90 WThTERT cells. Taken together, we have elucidated that MT-hTers induce double-stranded DNA breaks (DSBs)-like damages in telomerase-positive IMR90 WThTERT cells following phosphorylation of ATM and p53 via suppression of TRF2 which eventually may have led to apoptosis via elevation of GADD45γ.

2011-05-29 | GSE24975 | GEO

Phenotype specific analyses of p53 reveal distinct regulatory mechanism for chronically activated p53

Project description:microarray analysis with and without sh-p53 in IMR90 (normal human diploid fiborblasts) Phenotypes were created by overexpression of RasG12V, E1A/RasG12V in IMR90 cells, in growing IMR90, inr quiescent IMR90 cells (3 days confluence) and 24 or 48 hours Etoposide treated IMR90 cells were subjected to lentiviral knockdown of p53 or vector

2015-02-27 | E-GEOD-53379 | biostudies-arrayexpress

Phenotype specific analyses of p53 reveal distinct regulatory mechanism for chronically activated p53

Project description:p53 ChIP seq and Histone mark ChIP Seq data in IMR90 (normal human diploid fibroblasts) Phenotypes were created by overexpression of RasG12V, E1A/RasG12V in IMR90 cells, growing IMR90 and 24 hour Etoposide treated IMR90 cells were subjected to p53 and histone mark ChIP Seq

2015-03-02 | E-GEOD-53491 | biostudies-arrayexpress

Chromatin dynamics of p53 binding sites in IMR90

Project description:We report the chromatin modification dynamics at p53 binding sites upon treatment with DMSO or nutlin3-a (5uM) in IMR90 human lung fibroblasts using ChIP-seq and RNA-seq analyses. We assessed the genomewide changes in H3, H3K4me3, H3K4me2, H3K4me1, H3K27ac, H4K16ac, RNA polymerase II, and p53 in response to p53 activation.

2014-11-12 | GSE58740 | GEO

Mutated RNA component of the telomerase induces apoptosis via GADD45-? in hTERT-overexpressing primary fibroblasts

Project description:Mutant template human telomerase RNAs (MT-hTers) have been shown to induce apoptosis in various cancerous cells that have high telomerase activity. However, the exact mechanisms by which MT-hTers inhibit the growth of cancer cells and affect normal somatic cells remain largely unknown. To determine the effects of MT-hTers on normal cells, MT-hTer-47A and -AU5 were introduced into IMR90 primary lung fibroblasts that have very low endogenous hTERT levels. Growth of IMR90 cells following MT-hTers infection was not impaired, however, cell proliferation of IMR90 wild-type hTERT (WT-hTERT) cells under MT-hTers-47A and -AU5 treatment was inhibited and increased cell death was observed. FACS analysis also showed that these cells underwent apoptosis. Confocal microscopy revealed that MT-hTers induced DNA damage foci, i.e., 53BP1 and ?-H2AX, in immortalized IMR90 WT-hTERT cells. Microarray analysis of the IMR90 WT-hTERT MT-hTer-47A and -AU5 versus IMR90 MT-hTer-47A and -AU5 revealed that GADD45-? was significantly elevated, and this result was further confirmed following RT-PCR and real time PCR assays. Moreover, we have showed that MT-hTers induce ATM phosphorylation at Ser 1981 in IMR90 WThTERT cells, and Western analysis revealed high levels of phospho p53 expression in these cells following activation of ATM. Our results also suggest that p53-dependent apoptosis in MT-hTers-infected IMR90 WT-hTERT cells could be due to a decreased expression of TRF2. Taken together, we propose a model that MT-hTers induce DSBs-like damages and trigger programmed cell death in IMR90 WT-hTERT cells following ATM-mediated phosphorylation of p53, which in turn upregulate GADD45-?, ultimately leading to apoptosis. MT-hTer-47A and -AU5 were introduced into IMR90 primary lung fibroblasts and immortalized IMR90 WT-hTERT cells. Through microarray analysis, gene expression of MT-hTer-infected IMR90 WT-hTERT cells were compared against MT-hTer-infected IMR90 control cells.

2011-05-28 | E-GEOD-24975 | biostudies-arrayexpress

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