A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth

Wang Q, Li W, Liu XS, Carroll JS, Jänne OA, Keeton EK, Chinnaiyan AM, Pienta KJ, Brown M.

Androgen receptor (AR) is a ligand-dependent transcription factor that plays a key role in prostate cancer. Little is known about the nature of AR cis-regulatory sites in the human genome. We have mapped the AR binding regions on two chromosomes in human prostate cancer cells by combining chromatin immunoprecipitation (ChIP) with tiled oligonucleotide microarrays. We find that the majority of AR binding regions contain noncanonical AR-responsive elements (AREs). Importantly, we identify a noncanonical ARE as a cis-regulatory target of AR action in TMPRSS2, a gene fused to ETS transcription factors in the majority of prostate cancers. In addition, through the presence of enriched DNA-binding motifs, we find other transcription factors including GATA2 and Oct1 that cooperate in mediating the androgen response. These collaborating factors, together with AR, form a regulatory hierarchy that governs androgen-dependent gene expression and prostate cancer growth and offer potential new opportunities for therapeutic intervention.

Network motif analysis of a multi-mode genetic-interaction network

R James Taylor , Andrew F Siegel and Timothy Galitski
http://genomebiology.com/2007/8/8/R160

Abstract:

Different modes of genetic interaction indicate different functional relationships between genes. The extraction of biological information from dense multi-mode genetic-interaction networks demands appropriate statistical and computational methods. We developed such methods and implemented them in open-source software. Motifs extracted from multi-mode genetic-interaction networks form functional subnetworks, highlight genes dominating these subnetworks, and reveal genetic reflections of the underlying biochemical system.

Celsius: a community resource for Affymetrix microarray data

(UCLA) Allen Day, Marc RJ Carlson, Jun Dong , Brian D O’Connor and Stanley F Nelson

Celsius is a data warehousing system to aggregate Affymetrix CEL files and associated metadata. It provides mechanisms for importing, storing, querying, and exporting large volumes of primary and pre-processed microarray data. Celsius contains ten billion assay measurements and affiliated metadata. It is the largest publicly available source of Affymetrix microarray data, and through sheer volume enables a sophisticated, broad view of transcription that has previously not been possible.

Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites

Xiaohui Xie, Tarjei S. Mikkelsen^,, Andreas Gnirke, Kerstin Lindblad-Toh, Manolis Kellis^,, and Eric S. Lander^,¶,||,

Conserved noncoding elements (CNEs) constitute the majority of sequences under purifying selection in the human genome, yet their function remains largely unknown. Experimental evidence suggests that many of these elements play regulatory roles, but little is known about regulatory motifs contained within them. Here we describe a systematic approach to discover and characterize regulatory motifs within mammalian CNEs by searching for long motifs (12–22 nt) with significant enrichment in CNEs and studying their biochemical and genomic properties. Our analysis identifies 233 long motifs (LMs), matching a total of 60,000 conserved instances across the human genome. These motifs include 16 previously known regulatory elements, such as the histone 3′-UTR motif and the neuron-restrictive silencer element, as well as striking examples of novel functional elements. The most highly enriched motif (LM1) corresponds to the X-box motif known from yeast and nematode. We show that it is bound by the RFX1 protein and identify thousands of conserved motif instances, suggesting a broad role for the RFX family in gene regulation. A second group of motifs (LM2*) does not match any previously known motif. We demonstrate by biochemical and computational methods that it defines a binding site for the CTCF protein, which is involved in insulator function to limit the spread of gene activation. We identify nearly 15,000 conserved sites that likely serve as insulators, and we show that nearby genes separated by predicted CTCF sites show markedly reduced correlation in gene expression. These sites may thus partition the human genome into domains of expression.

Discovering transcriptional regulatory regions in Drosophila by a nonalignment method for phylogenetic footprinting

Alona Sosinsky^*,,, Barry Honig^*,,,, Richard S. Mann, and Andrea Califano

The functional annotation of the nonprotein-coding DNA of eukaryotic genomes is a problem of central importance. Phylogenetic footprinting methods, which attempt to identify functional regulatory regions by comparing orthologous genomic sequences of evolutionarily related species, have shown promising results. The main advantage of this class of approaches is that they do not require any knowledge of the regulating transcription factors. Here we describe a method called Enhancer Detection using only Genomic Information (EDGI), which integrates a traditional motif-discovery algorithm with a local permutation-clustering algorithm. Together, they can identify large regulatory elements (e.g., enhancers) as evolutionarily conserved order-independent clusters of short conserved motifs. We show that EDGI can distinguish between established sets of known enhancers and nonenhancers with 88% accuracy, rivaling predictions by methods that rely on the knowledge of the regulating transcription factors and their DNA-binding specificities. We tested EDGI’s performance on a set of Drosophila genomes. Our results demonstrate that comparative genomic analysis of multiple closely related species has substantial power to identify key functional elements without additional biological knowledge.

Enhancing genome annotation with chromatin

A new approach that scans the modification states of histones along the chromosome allows the identification of enhancer elements in the complex genomes of higher eukaryotes. This is an important step in the functional annotation of the genome.

Link

Stochastic gene expression: from single molecules to the proteome

Benjamin B Kaufmann^{1, 2} and Alexander van Oudenaarden^1,

¹Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
²Division of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA

Available online 20 February 2007.

Protein production involves a series of stochastic chemical steps. One consequence of this fact is that the copy number of any given protein varies substantially from cell to cell, even within isogenic populations. Recent experiments have measured this variation for thousands of different proteins, revealing a linear relationship between variance and mean level of expression for much of the proteome. This simple relationship is frequently thought to arise from the random production and degradation of mRNAs, but several lines of evidence suggest that infrequent gene activation events also bear responsibility. In support of the latter hypothesis, single-molecule experiments have demonstrated that mRNA transcripts are often produced in large bursts. Moreover, the temporal pattern of these bursts appears to be correlated for chromosomally proximal genes, suggesting the existence of an upstream player.

Enrichment or depletion of a GO category within a class of genes: which test?

discusses approximate and exact tests for GO enrichment/depletion, the associated p-value computations, and Table 1 contains over 20 GO tools packages.

Bioinformatics 2007 23(4):401-407

http://bioinformatics.oxfordjournals.org/cgi/content/full/23/4/401

CHD5 Is a Tumor Suppressor at Human 1p36

The authors at Cold Spring Harbor Laboratory functionally identify chromodomain helicase DNA binding domain 5 (Chd5) as a tumor suppressor that controls proliferation, apoptosis, and senescence via the p19^Arf/p53 pathway. They demonstrate that Chd5 functions as a tumor suppressor in vivo and implicate deletion of CHD5 in human cancer.

Cell, Vol 128, 459-475, 09 February 2007

Mapping autism risk loci using genetic linkage and chromosomal rearrangements

The AGP also scanned DNA from these families for copy number variations (CNV), or sub-microscopic genomic insertions and deletions that scientists believe might be involved with this and other common diseases. The innovative combination of these two approaches implicates a previously unidentified region of chromosome 11, and neurexin 1, a member of a family of genes believed to be important in neuronal contact and communication, among other regions and genes in the genome. The neurexin finding in particular highlights a special group of neurons, called glutamate neurons, and the genes affecting their development and function, suggesting they play a critical role in autism spectrum disorders.

Nature Genetics (18 Feb 2007) Article