Enrichment analysis is a popular method for analyzing gene sets generated by genome-wide experiments. Here we present a significant update to one of the tools in this domain called Enrichr. Enrichr currently contains a large collection of diverse gene set libraries available for analysis and download. In total, Enrichr currently contains 180 184 annotated gene sets from 102 gene set libraries. New features have been added to Enrichr including the ability to submit fuzzy sets, upload BED files, improved application programming interface and visualization of the results as clustergrams. Overall, Enrichr is a comprehensive resource for curated gene sets and a search engine that accumulates biological knowledge for further biological discoveries. Enrichr is freely available at: http://amp.pharm.mssm.edu/Enrichr.

Enrichr: a comprehensive gene set enrichment analysis web server 2016 update

System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes/proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries. While many enrichment analysis tools and gene-set libraries databases have been developed, there is still room for improvement. Here, we present Enrichr, an integrative web-based and mobile software application that includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. We applied Enrichr to analyze nine cancer cell lines by comparing their enrichment signatures to the enrichment signatures of matched normal tissues. We observed a common pattern of up regulation of the polycomb group PRC2 and enrichment for the histone mark H3K27me3 in many cancer cell lines, as well as alterations in Toll-like receptor and interlukin signaling in K562 cells when compared with normal myeloid CD33+ cells. Such analyses provide global visualization of critical differences between normal tissues and cancer cell lines but can be applied to many other scenarios. Enrichr is an easy to use intuitive enrichment analysis web-based tool providing various types of visualization summaries of collective functions of gene lists. Enrichr is open source and freely available online at: http://amp.pharm.mssm.edu/Enrichr
 .

/pdf/enrichr-interactive-and-collaborative-html5-gene-list-1dn7g68rn1.pdf

Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

NF‐κB is responsible for upregulating gene products that control cell survival. In this study, we demonstrate that SIRT1, a nicotinamide adenosine dinucleotide‐dependent histone deacetylase, regulates the transcriptional activity of NF‐κB. SIRT1, the mammalian ortholog of the yeast SIR2 (Silencing Information Regulator) and a member of the Sirtuin family, has been implicated in modulating transcriptional silencing and cell survival. SIRT1 physically interacts with the RelA/p65 subunit of NF‐κB and inhibits transcription by deacetylating RelA/p65 at lysine 310. Treatment of cells with resveratrol, a small‐molecule agonist of Sirtuin activity, potentiates chromatin‐associated SIRT1 protein on the cIAP‐2 promoter region, an effect that correlates with a loss of NF‐κB‐regulated gene expression and sensitization of cells to TNFα‐induced apoptosis. While SIRT1 is capable of protecting cells from p53‐induced apoptosis, our work provides evidence that SIRT1 activity augments apoptosis in response to TNFα by the ability of the deacetylase to inhibit the transactivation potential of the RelA/p65 protein.

/pdf/modulation-of-nf-kb-dependent-transcription-and-cell-4tfbiib05o.pdf

Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase

The normal prostate and early-stage prostate cancers depend on androgens for growth and survival, and androgen ablation therapy causes them to regress. Cancers that are not cured by surgery eventually become androgen independent, rendering anti-androgen therapy ineffective. But how does androgen independence arise? We predict that understanding the pathways that lead to the development of androgen-independent prostate cancer will pave the way to effective therapies for these, at present, untreatable cancers.

The development of androgen-independent prostate cancer

Nuclear receptor coregulators are coactivators or corepressors that are required by nuclear receptors for efficient transcripitonal regulation. In this context, we define coactivators, broadly, as molecules that interact with nuclear receptors and enhance their transactivation. Analogously, we refer to nuclear receptor corepressors as factors that interact with nuclear receptors and lower the transcription rate at their target genes. Most coregulators are, by definition, rate limiting for nuclear receptor activation and repression, but do not significantly alter basal transcription. Recent data have indicated multiple modes of action of coregulators, including direct interactions with basal transcription factors and covalent modification of histones and other proteins. Reflecting this functional diversity, many coregulators exist in distinct steady state precomplexes, which are thought to associate in promoter-specific configurations. In addition, these factors may function as molecular gates to enable integration of diverse signal transduction pathways at nuclear receptor-regulated promoters. This review will summarize selected aspects of our current knowledge of the cellular and molecular biology of nuclear receptor coregulators.

/pdf/nuclear-receptor-coregulators-cellular-and-molecular-biology-4dk45po37o.pdf

Nuclear receptor coregulators: cellular and molecular biology.

A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex.

Analysis of the Human Endogenous Coregulator Complexome

Nuclear receptor (NR) coregulators (coactivators and corepressors) are essential elements in regulating nuclear receptor-mediated transcription. In a little more than a decade since their discovery, these proteins have been studied mechanistically and reveal that the regulation of transcription is a highly controlled and complex process. Because of their central role in regulating NR-mediated transcription and in coordinating intercompartmental metabolic processes, disruptions in coregulator biology can lead to pathological states. To date, the extent to which they are involved in human disease has not been widely appreciated. In a complete literature survey, we have identified nearly 300 distinct coregulators, revealing that a great variety of enzymatic and regulatory capabilities exist for NRs to regulate transcription and other cellular events. Here, we substantiate that coregulators are broadly implicated in human pathological states and will be of growing future interest in clinical medicine.

/pdf/nuclear-receptor-coregulators-and-human-disease-2fus8uh67e.pdf

Nuclear receptor coregulators and human disease.

Completion of the Rattus norvegicus genome sequence enabled a global inventory and analysis of the nuclear receptors (NRs) in three mammalian species. Forty-nine NR members were found in mouse, 48 in human. Forty-seven were found in the rat, with gaps at the locations expected for the other two. Pairwise comparisons of their distribution in rat, mouse, and human identified 11 syntenic NR gene blocks, including three small clusters of two or three closely related genes, each spanning 40 kb to 1700 kb. The exon structure of the ligand-binding domain suggests that exon shuffling has played a role in the evolution of this family. An invariant splice junction in all members of the NR family except LXRbeta suggests a functional role for the intron. The ligand-binding domains of PXR and CAR are among the most divergent in the family. Their higher nucleotide substitution rates may be related to the central role played by these two NRs in the metabolism of the foreign compounds and may have resulted from limited positive selection.

/pdf/genomic-analysis-of-the-nuclear-receptor-family-new-insights-31cv6noinx.pdf

Rainer B. Lanz

Papers

Nuclear receptor coregulators: cellular and molecular biology.

A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex.

Analysis of the Human Endogenous Coregulator Complexome

Nuclear receptor coregulators and human disease.

Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome