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Genome-wide analysis of tumor suppressive programs during p53-induced regression of Myc-driven lymphomas [DNaseI-seq]

ABSTRACT: The tumor suppressor p53 is a transcription factor that controls the response to stress. Here, we dissected the transcriptional programs triggered upon restoration of p53 in Myc-driven lymphomas, based on the integrated analysis of p53 genomic occupancy and gene regulation. p53 binding sites were identified at promoters and enhancers, both characterized by the pre-existence of active chromatin marks. p53 recruitment at these sites was mainly mediated through protein-protein or protein-chromatin interactions and, only for a small fraction, through recognition of the 20 base-pair p53 consensus motif. At promoters, p53 binding to the consensus motif was associated with gene induction, but not repression, indicating that the latter was most likely indirect. p53 also targeted unmarked distal sites devoid of activation marks, at which binding was prevalently driven by recognition of the consensus motif. At all sites, our data highlighted a functional role for the canonical, unsplit consensus element, but did not provide evidence for p53 recruitment by split motifs. Altogether, our data highlight key features of genome recognition by p53 and provide unprecedented insight into the pathways associated with p53 re-activation and tumor regression.

ORGANISM(S): Mus musculus

PROVIDER: GSE80193 | GEO | 2017/02/14

SECONDARY ACCESSION(S): PRJNA318257

REPOSITORIES: GEO

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Project description:Recent genome-scale ChIP-chip studies of transcription factors have shown that a low percentage of experimentally determined binding sites contain the consensus motif for the immunoprecipitated factor. In most cases, differences between in vivo target sites that contain or lack a consensus motif have not been explored. We have previously shown that most sites to which E2F family members are bound in vivo do not contain E2F consensus motifs. The main purpose of this study was to develop an understanding of how E2F binding specificity is achieved in vivo. In particular, we have addressed how E2F family members are recruited to core promoter regions that lack a consensus motif and are excluded from other regions that contain a consensus motif. Using promoter and ENCODE arrays, we have shown that the predominant factors specifying whether E2F is recruited to an in vivo binding site are a) the site must be in a core promoter and b) the promoter region must be utilized as a promoter by the transcriptional machinery in that particular cell type. We have tested three models for recruitment of E2F to core promoters lacking a consensus site, including a) indirect recruitment, b) looping to the core promoter mediated by an E2F bound to a distal consensus motif, and c) assisted binding of E2F to a site that weakly resembles an E2F consensus motif within the core promoter. To test these models, we developed a new in vivo assay, termed eChIP, which allows analysis of transcription factor binding to isolated promoter fragments. Our findings suggest that in vivo a) the presence of a consensus motif is not sufficient to recruit E2Fs, b) E2Fs can bind to isolated regions that lack a consensus motif, and c) binding can require regions other than the best match to the E2F PWM in the core promoter. Keywords: E2F, ChIP-chip, transcription factor binding, consensus motifs 37 ChIP-chip arrays (of these, 14 array sets are biological duplicates). 22 samples are included in this series, the rest can be found in supplementary info to the following papers: Xu 2007, Jin 2006, Komashko 2008

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Genome-wide analysis of tumor suppressive programs during p53-induced regression of Myc-driven lymphomas [DNaseI-seq]

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