p53 induces distinct epigenetic states at its direct target promoters

Lukas Vrba, Damian J. Junk, Petr Novak, Bernard W Futscher

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background: The tumor suppressor protein p53 is a transcription factor that is mutated in many cancers. Regulation of gene expression by binding of wild-type p53 to its target sites is accompanied by changes in epigenetic marks like histone acetylation. We studied DNA binding and epigenetic changes induced by wild-type and mutant p53 in non-malignant hTERT-immortalized human mammary epithelial cells overexpressing either wild-type p53 or one of four p53 mutants (R175H, R249S, R273H and R280K) on a wild-type p53 background. Results: Using chromatin immunoprecipitation coupled to a 13,000 human promoter microarray, we found that wild-type p53 bound 197 promoters on the microarray including known and novel p53 targets. Of these p53 targets only 20% showed a concomitant increase in histone acetylation, which was linked to increased gene expression, while 80% of targets showed no changes in histone acetylation. We did not observe any decreases in histone acetylation in genes directly bound by wild-type p53. DNA binding in samples expressing mutant p53 was reduced over 95% relative to wild-type p53 and very few changes in histone acetylation and no changes in DNA methylation were observed in mutant p53 expressing samples. Conclusion: We conclude that wild-type p53 induces transcription of target genes by binding to DNA and differential induction of histone acetylation at target promoters. Several new wild-type p53 target genes, including DGKZ, FBXO22 and GDF9, were found. DNA binding of wild-type p53 is highly compromised if mutant p53 is present due to interaction of both p53 forms resulting in no direct effect on epigenetic marks.

Original languageEnglish (US)
Article number486
JournalBMC Genomics
Volume9
DOIs
StatePublished - Oct 15 2008

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Acetylation
Epigenomics
Histones
DNA
Histone Code
Tumor Suppressor Protein p53
Chromatin Immunoprecipitation
p53 Genes
Gene Expression Regulation
DNA Methylation
Genes
Breast
Transcription Factors
Epithelial Cells
Gene Expression
Neoplasms

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

p53 induces distinct epigenetic states at its direct target promoters. / Vrba, Lukas; Junk, Damian J.; Novak, Petr; Futscher, Bernard W.

In: BMC Genomics, Vol. 9, 486, 15.10.2008.

Research output: Contribution to journalArticle

Vrba, Lukas ; Junk, Damian J. ; Novak, Petr ; Futscher, Bernard W. / p53 induces distinct epigenetic states at its direct target promoters. In: BMC Genomics. 2008 ; Vol. 9.
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abstract = "Background: The tumor suppressor protein p53 is a transcription factor that is mutated in many cancers. Regulation of gene expression by binding of wild-type p53 to its target sites is accompanied by changes in epigenetic marks like histone acetylation. We studied DNA binding and epigenetic changes induced by wild-type and mutant p53 in non-malignant hTERT-immortalized human mammary epithelial cells overexpressing either wild-type p53 or one of four p53 mutants (R175H, R249S, R273H and R280K) on a wild-type p53 background. Results: Using chromatin immunoprecipitation coupled to a 13,000 human promoter microarray, we found that wild-type p53 bound 197 promoters on the microarray including known and novel p53 targets. Of these p53 targets only 20{\%} showed a concomitant increase in histone acetylation, which was linked to increased gene expression, while 80{\%} of targets showed no changes in histone acetylation. We did not observe any decreases in histone acetylation in genes directly bound by wild-type p53. DNA binding in samples expressing mutant p53 was reduced over 95{\%} relative to wild-type p53 and very few changes in histone acetylation and no changes in DNA methylation were observed in mutant p53 expressing samples. Conclusion: We conclude that wild-type p53 induces transcription of target genes by binding to DNA and differential induction of histone acetylation at target promoters. Several new wild-type p53 target genes, including DGKZ, FBXO22 and GDF9, were found. DNA binding of wild-type p53 is highly compromised if mutant p53 is present due to interaction of both p53 forms resulting in no direct effect on epigenetic marks.",
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