Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution.

To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements.

A comparative encyclopedia of DNA elements in the mouse genome.

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization.

Developmental fate and cellular maturity encoded in human regulatory DNA landscapes.

Cellular-state information between generations of developing cells may be propagated via regulatory regions. We report consistent patterns of gain and loss of DNase I-hypersensitive sites (DHSs) as cells progress from embryonic stem cells (ESCs) to terminal fates. DHS patterns alone convey rich information about cell fate and lineage relationships distinct from information conveyed by gene expression.

[Use of oral oxybutynin at 7.5 mg per day in primary hyperhidrosis].

Oxybutynin is being increasingly being prescribed in the treatment of hyperhidrosis but currently, there is no precise dosage for this treatment. Nine patients were treated for primary hyperhidrosis resistant to conventional therapies with oxybutynin between January to May 2010. The treatment was progressively increased at 7.

Systematic localization of common disease-associated variation in regulatory DNA.

Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes.

An expansive human regulatory lexicon encoded in transcription factor footprints.

Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements.

The accessible chromatin landscape of the human genome.

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.

BEDOPS: high-performance genomic feature operations.

Unlabelled: The large and growing number of genome-wide datasets highlights the need for high-performance feature analysis and data comparison methods, in addition to efficient data storage and retrieval techniques. We introduce BEDOPS, a software suite for common genomic analysis tasks which offers improved flexibility, scalability and execution time characteristics over previously published packages. The suite includes a utility to compress large inputs into a lossless format that can provide greater space savings and faster data extractions than alternatives.

Gammaretroviral vector integration occurs overwhelmingly within and near DNase hypersensitive sites.

Concerns surrounding the oncogenic potential of recombinant gammaretroviral vectors has spurred a great deal of interest in vector integration site (VIS) preferences. Although gammaretroviral vectors exhibit a modest preference for integration near transcription start sites (TSS) of active genes, such associations only account for about a third of all VIS. Previous studies suggested a correlation between gammaretroviral VIS and DNase hypersensitive sites (DHS), which mark chromatin regions associated with cis-regulatory elements.

A thermodynamic approach to PCR primer design.

We developed a primer design method, Pythia, in which state of the art DNA binding affinity computations are directly integrated into the primer design process. We use chemical reaction equilibrium analysis to integrate multiple binding energy calculations into a conservative measure of polymerase chain reaction (PCR) efficiency, and a precomputed index on genomic sequences to evaluate primer specificity. We show that Pythia can design primers with success rates comparable with those of current methods, but yields much higher coverage in difficult genomic regions.

Assaying the regulatory potential of mammalian conserved non-coding sequences in human cells.

Background: Conserved non-coding sequences in the human genome are approximately tenfold more abundant than known genes, and have been hypothesized to mark the locations of cis-regulatory elements. However, the global contribution of conserved non-coding sequences to the transcriptional regulation of human genes is currently unknown. Deeply conserved elements shared between humans and teleost fish predominantly flank genes active during morphogenesis and are enriched for positive transcriptional regulatory elements.

Automated validation of polymerase chain reaction amplicon melting curves.

The polymerase chain reaction (PCR) is a fundamental tool of molecular biology. Quantitative PCR is the gold-standard methodology for determination of DNA copy numbers, quantitating transcription, and numerous other applications. A major barrier to large-scale application of PCR for quantitative genomic analyses is the current requirement for manual validation of individual PCRs to ensure generation of a single product.

Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays.

Localized accessibility of critical DNA sequences to the regulatory machinery is a key requirement for regulation of human genes. Here we describe a high-resolution, genome-scale approach for quantifying chromatin accessibility by measuring DNase I sensitivity as a continuous function of genome position using tiling DNA microarrays (DNase-array). We demonstrate this approach across 1% ( approximately 30 Mb) of the human genome, wherein we localized 2,690 classical DNase I hypersensitive sites with high sensitivity and specificity, and also mapped larger-scale patterns of chromatin architecture.

Automated validation of polymerase chain reactions using amplicon melting curves.

PCR, the polymerase chain reaction, is a fundamental tool of molecular biology. Quantitative PCR is the gold-standard methodology for determination of DNA copy numbers, quantitating transcription, and numerous other applications. A major barrier to large-scale application of PCR for quantitative genomic analyses is the current requirement for manual validation of individual PCR reactions to ensure generation of a single product.

[Management of patients admitted for acute myocardial infarction in France from 1995 to 2000: time to admission dependent improvement in outcome].

The in-hospital management and short- and long-term outcomes was assessed in 2 registries of consecutive patients admitted for acute myocardial infarction, 5 years apart, in France. The 2000 cohort was younger and with a less frequent history of cardiac diseases, but was more often diabetic and with anterior infarcts. Time to admission was actually longer in 2000 than in 1995 (median 5.

High-throughput localization of functional elements by quantitative chromatin profiling.

Identification of functional, noncoding elements that regulate transcription in the context of complex genomes is a major goal of modern biology. Localization of functionality to specific sequences is a requirement for genetic and computational studies. Here, we describe a generic approach, quantitative chromatin profiling, that uses quantitative analysis of in vivo chromatin structure over entire gene loci to rapidly and precisely localize cis-regulatory sequences and other functional modalities encoded by DNase I hypersensitive sites.

Discovery of functional noncoding elements by digital analysis of chromatin structure.

We developed a quantitative methodology, digital analysis of chromatin structure (DACS), for high-throughput, automated mapping of DNase I-hypersensitive sites and associated cis-regulatory sequences in the human and other complex genomes. We used 19/20-bp genomic DNA tags to localize individual DNase I cutting events in nuclear chromatin and produced approximately 257,000 tags from erythroid cells. Tags were mapped to the human genome, and a quantitative algorithm was applied to discriminate statistically significant clusters of independent DNase I cutting events.

Management and in-hospital outcome of patients with acute myocardial infarction admitted to intensive care units at the turn of the century: results from the French nationwide USIC 2000 registry.

Objective: To assess actual practices and in-hospital outcome of patients with acute myocardial infarction on a nationwide scale.

Methods: Of 443 intensive care units in France, 369 (83%) prospectively collected data on all cases of infarction (within < 48 hours of symptom onset) in November 2000.

Results: 2320 patients (median age 68 years, 73% men) were included, of whom 83% had ST segment elevation infarction (STEMI).

Genome-wide identification of DNaseI hypersensitive sites using active chromatin sequence libraries.

Comprehensive identification of sequences that regulate transcription is one of the major goals of genome biology. Focal alteration in chromatin structure in vivo, detectable through hypersensitivity to DNaseI and other nucleases, is the sine qua non of a diverse cast of transcriptional regulatory elements including enhancers, promoters, insulators, and locus control regions. We developed an approach for genome-scale identification of DNaseI hypersensitive sites (HSs) via isolation and cloning of in vivo DNaseI cleavage sites to create libraries of active chromatin sequences (ACSs).

[Evolution of the management and outcomes of patients admitted for acute myocardial infarction in France from 1995 to 2000: data from the USIK 1995 and USIC 2000 nationwide registries].

We assessed the in-hospital management and short- and long-term outcomes of two series of patients admitted for acute myocardial infarction, 5 years apart, in France. The most recent cohort was younger and with a less frequent history of cardiac diseases, but was more often diabetic and with anterior infarcts. Five-day mortality significantly improved from 7.

[Handipark: a simple test of the impact of Parkinson's disease on activities of daily living].

Handipark, a new score for measuring the impact of Parkinson's disease on daily life activities is presented. The global score ranging from 1 to 10 (without half points) is easy to determine. For a given patient, the score takes into account 5 items describing the global impact of the disease;Inter- and intra-observer reproducibility were determined.

[Descriptive epidemiological study of acne on scholar pupils in France during autumn 1996].

Background: Acne is the most common symptom prompting patients to consult a dermatologist. No previous study has been conducted in France to determine the prevalence of acne and describe the main epidemiological features.

Subjects And Methods: A cross sectional study was conducted in November 1996 and included 913 school children aged 11 to 18 years.

[National survey on the use of induced labor by obstetricians. Study Group on Induced Labor].

Introduction: A strong rise in the use of induced labor has been observed in France. The aim of this work was to analyze the different methods used for achieving induction of labor and their implications.

Methods: One out of four French obstetricians were randomly selected to answer a questionnaire on their practice for achieving induction of labor.

Paraoxonase genotypes, lipoprotein lipase activity, and HDL.

Paraxonase, an enzyme associated with the high density lipoprotein (HDL) particle, hydrolyzes paraoxon, the active metabolite of the insecticide parathion. Several studies have shown that paraxonase levels in humans have a distribution characteristic of two alleles, one with low activity and the other with high activity. Paraoxonase also has arylesterase activity, which does not exhibit activity polymorphism and can therefore serve as an estimate of enzyme protein.