SET1 and p300 Act Synergistically, through Coupled Histone Modifications, in Transcriptional Activation by p53

• Published in: Cell 2013-07, Vol.154 (2), p.297-310
• Main Authors: Tang, Zhanyun, Chen, Wei-Yi, Shimada, Miho, Nguyen, Uyen T.T., Kim, Jaehoon, Sun, Xiao-Jian, Sengoku, Toru, McGinty, Robert K., Fernandez, Joseph P., Muir, Tom W., Roeder, Robert G.
• Format: Article
• Language: English
• Subjects: Acetylation; Amino Acid Sequence; chromatin; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage; E1A-Associated p300 Protein - metabolism; genes; HCT116 Cells; Histone Code; Histone-Lysine N-Methyltransferase - metabolism; histones; Histones - metabolism; Humans; in vitro studies; Methylation; Molecular Sequence Data; Multiprotein Complexes - metabolism; transcription; Transcription, Genetic; Transcriptional Activation; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.06.027

The H3K4me3 mark in chromatin is closely correlated with actively transcribed genes, although the mechanisms involved in its generation and function are not fully understood. In vitro studies with recombinant chromatin and purified human factors demonstrate a robust SET1 complex (SET1C)-mediated H3K4 trimethylation that is dependent upon p53- and p300-mediated H3 acetylation, a corresponding SET1C-mediated enhancement of p53- and p300-dependent transcription that reflects a primary effect of SET1C through H3K4 trimethylation, and direct SET1C-p53 and SET1C-p300 interactions indicative of a targeted recruitment mechanism. Complementary cell-based assays demonstrate a DNA-damage-induced p53-SET1C interaction, a corresponding enrichment of SET1C and H3K4me3 on a p53 target gene (p21/WAF1), and a corresponding codependency of H3K4 trimethylation and transcription upon p300 and SET1C. These results establish a mechanism in which SET1C and p300 act cooperatively, through direct interactions and coupled histone modifications, to facilitate the function of p53. [Display omitted] •SET1C-mediated H3K4me3 is enhanced by p53- and p300-dependent H3 acetylation•Crosstalk between H3 acetylation and H3K4 methylation requires the p300 bromodomain•H3K4me3 plays a causal role in p53- and p300-dependent transcription•p300 regulates the dynamics of H3K4 methylation on p21/WAF1 in a DNA-damage response Through direct interactions between p300, SET1C, and acetylated H3, p300-dependent acetylation of H3 enhances SET1C-mediated H3K4 trimethylation at p53 target genes. In this way, the two histone modifications collaborate to enhance the p53 transcriptional response.