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Integrative Genomic Analysis Reveals Widespread Enhancer Regulation by p53 in Response to DNA Damage

ABSTRACT: The tumor suppressor p53 has been studied extensively as a direct transcriptional activator of protein-coding genes. Recent studies, however, have shed light on novel regulatory functions of p53 within noncoding regions of the genome. Here, we use a systematic approach that integrates transcriptome-wide differential expression analysis, genome-wide p53 binding profiles, chromatin state maps, and additional genomic features to characterize the global regulatory roles of p53 in response to DNA damage in both human and mouse fibroblast models. In addition to known p53 targets, we identify many previously unappreciated mRNAs and long noncoding RNAs that are regulated by p53. Moreover, we find that p53 binding events occur predominantly within enhancer elements in both human and mouse systems. The ability to modulate enhancer activity offers an additional layer of complexity to the p53 network and greatly expands the diversity of genomic elements that are directly regulated by p53.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE55727 | GEO | 2015/04/18

SECONDARY ACCESSION(S): PRJNA240784

REPOSITORIES: GEO

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Integrative Genomic Analysis Reveals Widespread Enhancer Regulation by p53 in Response to DNA Damage

Project description:The tumor suppressor p53 has been studied extensively as a direct transcriptional activator of protein-coding genes. Recent studies, however, have shed light on novel regulatory functions of p53 within noncoding regions of the genome. Here, we use a systematic approach that integrates transcriptome-wide differential expression analysis, genome-wide p53 binding profiles, chromatin state maps, and additional genomic features to characterize the global regulatory roles of p53 in response to DNA damage in both human and mouse fibroblast models. In addition to known p53 targets, we identify many previously unappreciated mRNAs and long noncoding RNAs that are regulated by p53. Moreover, we find that p53 binding events occur predominantly within enhancer elements in both human and mouse systems. The ability to modulate enhancer activity offers an additional layer of complexity to the p53 network and greatly expands the diversity of genomic elements that are directly regulated by p53. Human and Mouse fibroblasts cultured in the presence or absence of doxorubicin followed by RNA-Seq (Human:2 cell lines, each condition in duplicate; Mouse:MEF cell line,each condition in triplicate) and p53 ChIP-Seq (Human:2 cell lines, input and IP for each; Mouse:MEF cell line, input and IP)

2015-04-18 | E-GEOD-55727 | biostudies-arrayexpress

Identification of Functional Regulatory Elements in the Human Genome Using Pooled CRISPR Screens

Project description:Genome-scale pooled CRISPR screens are powerful tools for identifying genetic dependencies across varied cellular processes. The vast majority of CRISPR screens reported to date have focused exclusively on the perturbation of protein-coding gene function. However, protein-coding genes comprise <2% of the sequence space in the human genome leaving a substantial portion of the genome uninterrogated. Noncoding regions of the genome harbor important regulatory elements (e.g. promoters, enhancers, suppressors) that influence cellular processes but high-throughput methods for evaluating their essentiality have yet to be established. Here, we describe a CRISPR-based screening approach that facilitates the functional profiling of thousands of noncoding regulatory elements in parallel. We selected the tumor suppressor p53 as a model system and designed a pooled CRISPR library targeting thousands of p53 binding sites throughout the genome. Following transduction into dCas9-KRAB-expressing cells we identified several regulatory elements that influence cell proliferation. Moreover, we uncovered multiple elements that are required for the p53-mediated DNA damage response. Surprisingly, many of these elements are located deep within intergenic regions of the genome that have no prior functional annotations. This work diversifies the applications for pooled CRISPR screens and provides a framework for future functional studies focused on noncoding regulatory elements.

2019-08-21 | GSE126320 | GEO

p53 Regulates Enhancer Accessibility and Activity in Response to DNA Damage

Project description:The tumor suppressor p53 is a well-characterized transcription factor that can bind gene promoters and regulate target gene transcription in response to DNA damage. Recent studies, however, have revealed that p53 binding events occur predominantly within regulatory enhancer elements. The effect of p53 binding on enhancer function has not been systematically evaluated. Here, we perform a genome-scale analysis of enhancer activity from p53-bound sequences using a series of massively parallel reporter assays (MPRAs) coupled with the assay for transpose-accessible chromatin (ATAC-Seq). We find that the majority of p53 bound sequences examined are potent regulators of enhancer activity during the DNA damage response. Enhancer regulation requires the presence of the p53 consensus sequence and results in significant induction of target gene transcription. Surprisingly, our analyses revealed that most p53-bound enhancers are located within regions of inaccessible chromatin. Many of these enhancers display significantly increased accessibility in response to DNA damage suggesting that p53 regulates their activity, in part, by altering local chromatin environments. The recognition and activation of inaccessible enhancers may contribute to the ability of the p53 network to function across the diverse chromatin landscapes of different cell and tissue types.

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Complementary Alu sequences mediate enhancer-promoter selectivity

Project description:Enhancers determine spatiotemporal gene expression programs by engaging with long-range promoters. However, it remains unknown how enhancers find their cognate promoters. We recently developed a RIC-seq technology to identify enhancer-promoter connectivity using pairwise interacting enhancer RNAs and promoter-derived noncoding RNAs in HeLa cells. Here, we apply this technology to generate high-confidence enhancer-promoter RNA interaction (EPRI) maps in six additional cell lines. Using these maps, we discover that 37.9% of the enhancer-promoter RNA interaction sites are overlapped with Alu sequences. These pairwise interacting Alu and non-Alu RNA sequences tend to be complementary and potentially form duplexes. Knockout of Alu elements compromises enhancer-promoter looping, whereas Alu insertion or CRISPR-dCasRx-mediated Alu tethering to unregulated promoter RNAs can create new loops to homologous enhancers. Importantly, mapping 535,404 noncoding risk variants back to the EPRI maps enabled us to construct variant-to-function maps for interpreting their molecular functions, including 15,318 deletions or insertions in 11,677 Alu elements that affect 6,497 protein-coding genes. We further demonstrate that polymorphic Alu insertion at PTK2 enhancer can promote tumorigenesis. Our study uncovers a principle for determining enhancer-promoter pairing specificity and provides a framework to link noncoding risk variants to their molecular functions.

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Enhancer Cis Elements Instruct Promoter-Enhancer Interaction, Promoter-Enhancer Insulation and Compartmental Segregation

Project description:Enhancers harbor instructions encoded for the interactions between cis-elements and transcription factors to orchestrate lineage specific gene programs. Here we developed a modified method for chromosome conformation capture (3C), named MID Hi-C, to reveal how in mouse embryonic stem cells differential cooperation of enhancers and the chromatin remodeler BAF, as instructed by the underlying transcription factor motifs, modulate enhancer-promoter communication. We show that BAF-dependent enhancers permit genomic interactions beyond enhancer boundaries. BAF-dependent enhancers do not dictate genomic interactions within enhancer-promoter loop domains but rather act to instruct remote enhancer-promoter communication. In contrast, BAF-independent enhancers interact with promoter regions within tightly insulated enhancer-promoter loop domains that are marked by promoter and enhancer boundary elements. In addition, enhancer activeness modulated by BAF enforces compartment segregation. Based on these observations, we propose that enhancer cis elements instruct with great precision BAF-induced enhancer-promoter communication and compartmental segregation.

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Widespread Long-range Cis-Regulatory Elements in the Maize Genome

Project description:Genetic mapping studies on crops suggest that agronomic traits can be controlled by loci within the gene-distal intergenic space. Despite the biological importance and the potential agronomic utility of these intergenic loci, they remain virtually uncharacterized in all crop species to date. Here, we provide genetic, epigenomic, and functional molecular evidence supporting the widespread existence of gene-distal (hereafter, distal) loci which act as long-range transcriptional cis-regulatory elements (CREs) in the maize genome. Such loci are enriched for euchromatic chromatin features that suggest their regulatory functions. Chromatin loops link together putative CREs with genes and recapitulate eQTL-gene interactions. Additionally, putative CREs display elevated transcriptional enhancer activities, as measured by STARR-seq. These results provide functional support for the widespread existence of CREs which act over large genomic distances to modulate gene expression.

2019-09-19 | GSE120304 | GEO

p53-bound enhancer elements require locally acting transcription factors

Project description:p53-bound enhancer elements require locally acting transcription factors

| PRJNA565047 | ENA

Integrative Genomic Analysis Reveals Widespread Enhancer Regulation by p53 in Response to DNA Damage

Project description:Integrative Genomic Analysis Reveals Widespread Enhancer Regulation by p53 in Response to DNA Damage

| PRJNA240784 | ENA

Rho directs widespread termination of intragenic and stable RNA transcription

Project description:The transcription termination factor Rho is a global regulator of RNA polymerase (RNAP). Although individual Rho-dependent terminators have been studied extensively, less is known about the sites of RNAP regulation by Rho on a genome-wide scale. Using chromatin immunoprecipitation and microarrays (ChIP-chip), we examined changes in the distribution of Escherichia coli RNAP in response to the Rho-specific inhibitor bicyclomycin (BCM). We found ~200 Rho-terminated loci that were divided evenly into two classes: intergenic (at the ends of genes) and intragenic (within genes). The intergenic class contained noncoding RNAs such as small RNAs (sRNAs) and transfer RNAs (tRNAs), establishing a previously unappreciated role of Rho in termination of stable RNA synthesis. The intragenic class of terminators included a novel set of short antisense transcripts, as judged by a shift in the distribution of RNAP in BCM-treated cells that was opposite to the direction of the corresponding gene. These Rho-terminated antisense transcripts point to a novel role of noncoding transcription in E. coli gene regulation that may resemble the ubiquitous noncoding transcription recently found to play myriad roles in eukaryotic gene regulation. Chromatin immunoprecipitation (ChIP) experiments were performed using antibodies against RNA polymerase (Beta or Beta' subunit) in cells treated with 20ug/ml bicyclomycin or untreated cells. Differentially labeled ChIP DNA and genomic DNA were competitively hybridized to an E. coli K-12 MG1655 tiling array with overlapping probes at ~12bp spacing across the entire genome. The series contains 4 datasets.

2010-05-18 | E-GEOD-16562 | biostudies-arrayexpress

Subtelomeric p53 Binding Prevents Accumulation of DNA Damage at Human Telomeres

Project description:Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non-canonical p53 binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non-canonical subtelomeric p53 binding sites conferred transcription enhancer-like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere-repeat containing RNA (TERRA). p53 suppressed formation of telomere-associated Î³H2AX and prevented telomere DNA degradation in response to DNA damage stress. Our findings indicate that p53 provides a direct chromatin-associated protection to human telomeres, as well as other fragile genomic sites. We propose that p53-associated chromatin modifications enhance local DNA repair or protection to provide a previously unrecognized tumor suppressor function of p53. p53 binding was analyzed by ChIP-Seq in HCT116 cells treated with camptothecin or untreated control.

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