RESUMO
The p53 transcription factor confers its potent tumor suppressor functions primarily through the regulation of a large network of target genes. The recent explosion of next generation sequencing protocols has enabled the study of the p53 gene regulatory network (GRN) and underlying mechanisms at an unprecedented depth and scale, helping us to understand precisely how p53 controls gene regulation. Here, we discuss our current understanding of where and how p53 binds to DNA and chromatin, its pioneer-like role, and how this affects gene regulation. We provide an overview of the p53 GRN and the direct and indirect mechanisms through which p53 affects gene regulation. In particular, we focus on delineating the ubiquitous and cell type-specific network of regulatory elements that p53 engages; reviewing our understanding of how, where, and when p53 binds to DNA and the mechanisms through which these events regulate transcription. Finally, we discuss the evolution of the p53 GRN and how recent work has revealed remarkable differences between vertebrates, which are of particular importance to cancer researchers using mouse models.
Assuntos
Cromatina/metabolismo , DNA/metabolismo , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Proteína Supressora de Tumor p53/fisiologia , Animais , Sítios de Ligação , Linhagem Celular , Humanos , Camundongos , Ligação Proteica , RatosRESUMO
p53 transcriptional networks are well-characterized in many organisms. However, a global understanding of requirements for in vivo p53 interactions with DNA and relationships with transcription across human biological systems in response to various p53 activating situations remains limited. Using a common analysis pipeline, we analyzed 41 data sets from genome-wide ChIP-seq studies of which 16 have associated gene expression data, including our recent primary data with normal human lymphocytes. The resulting extensive analysis, accessible at p53 BAER hub via the UCSC browser, provides a robust platform to characterize p53 binding throughout the human genome including direct influence on gene expression and underlying mechanisms. We establish the impact of spacers and mismatches from consensus on p53 binding in vivo and propose that once bound, neither significantly influences the likelihood of expression. Our rigorous approach revealed a large p53 genome-wide cistrome composed of >900 genes directly targeted by p53. Importantly, we identify a core cistrome signature composed of genes appearing in over half the data sets, and we identify signatures that are treatment- or cell-specific, demonstrating new functions for p53 in cell biology. Our analysis reveals a broad homeostatic role for human p53 that is relevant to both basic and translational studies.
Assuntos
Proteínas de Ligação a DNA/genética , Genoma Humano/genética , Transcrição Gênica , Proteína Supressora de Tumor p53/genética , DNA Intergênico/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica/genética , Genes/genética , Humanos , Linfócitos , Biossíntese de ProteínasRESUMO
Pest insects have a profound negative impact on agriculture and human health. Significant global losses of crops, stored agricultural products, timber and livestock can be attributed to damage and destruction by insects . Blood-feeding insects such as mosquitoes, flies and ticks transmit many of humanity's most devastating infectious diseases. Insect-borne diseases account for more than one million annual fatalities, and insect-associated illnesses surpass 300 million annual reported cases . The medical and economic impact of these animals can be ascribed in part to the sensitivity and selectivity of their olfactory systems, essential for location of their preferred plant and animal hosts.