p53 induces distinct epigenetic states at its direct target promoters
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Lukas Vrba1,4, Damian J Junk1,2, Petr Novak1,4 and Bernard W Futscher*1,2,3
- چاپ و سال / کشور: 2008
Description
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.
Published: 15 October 2008 BMC Genomics 2008, 9:486 doi:10.1186/1471-2164-9-486 Received: 24 June 2008 Accepted: 15 October 2008 This article is available from: http://www.biomedcentral.com/1471-2164/9/486
