Power-law-like distributions in biomedical publications and research funding

A search of the literature reveals that researchers study relatively few genes out of the total human genome

The Circadian Clock Gates the Intestinal Stem Cell Regenerative State

The intestine has evolved under constant environmental stresses, because an animal may ingest harmful pathogens or chemicals at any time during its lifespan. Following damage, intestinal stem cells (ISCs) regenerate the intestine by proliferating to replace dying cells. ISCs from diverse animals are remarkably similar, and the Wnt, Notch, and Hippo signaling pathways, important regulators of mammalian ISCs, are conserved from flies to humans. Unexpectedly, we identified the transcription factor period, a component of the circadian clock, to be critical for regeneration, which itself follows a circadian rhythm. We discovered hundreds of transcripts that are regulated by the clock during intestinal regeneration, including components of stress response and regeneration pathways. Disruption of clock components leads to arrhythmic ISC divisions, revealing their underappreciated role in the healing process

A functional map of NFκB signaling identifies novel modulators and multiple system controls

Using cell-based genomic screens and functional assays, positive and negative modulators of NFκB signaling were identified and mapped onto the known NFκB signaling cascade

Genome-Wide Expression Analysis in Drosophila Reveals Genes Controlling Circadian Behavior

In Drosophila, a number of key processes such as emergence from the pupal case, locomotor activity, feeding, olfaction, and aspects of mating behavior are under circadian regulation. Although we have a basic understanding of how the molecular oscillations take place, a clear link between gene regulation and downstream biological processes is still missing. To identify clock-controlled output genes, we have used an oligonucleotide-based high-density array that interrogates gene expression changes on a whole genome level. We found genes regulating various physiological processes to be under circadian transcriptional regulation, ranging from protein stability and degradation, signal transduction, heme metabolism, detoxification, and immunity. By comparing rhythmically expressed genes in the fly head and body, we found that the clock has adapted its output functions to the needs of each particular tissue, implying that tissue-specific regulation is superimposed on clock control of gene expression. Finally, taking full advantage of the fly as a model system, we have identified and characterized a cycling potassium channel protein as a key step in linking the transcriptional feedback loop to rhythmic locomotor behavior.Fil: Ceriani, Maria Fernanda. The Scripps Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Hogenesch, John B.. Genomics Institute of the Novartis Research Foundation; Estados UnidosFil: Yanovsky, Marcelo Javier. The Scripps Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Panda, Satchidananda. Genomics Institute of the Novartis Research Foundation; Estados Unidos. The Scripps Research Institute; Estados UnidosFil: Straume, Martin. University Of Virginia; Estados UnidosFil: Kay, Steve A.. Genomics Institute of the Novartis Research Foundation; Estados Unidos. The Scripps Research Institute; Estados Unido

The Local Edge Machine: inference of dynamic models of gene regulation

We present a novel approach, the Local Edge Machine, for the inference of regulatory interactions directly from time-series gene expression data. We demonstrate its performance, robustness, and scalability on in silico datasets with varying behaviors, sizes, and degrees of complexity. Moreover, we demonstrate its ability to incorporate biological prior information and make informative predictions on a well-characterized in vivo system using data from budding yeast that have been synchronized in the cell cycle. Finally, we use an atlas of transcription data in a mammalian circadian system to illustrate how the method can be used for discovery in the context of large complex networks.Department of Applied Mathematic

Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock

AbstractIn mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed ∼650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology

Network Features of the Mammalian Circadian Clock

The mammalian circadian clock is a cell-autonomous system that drives oscillations in behavior and physiology in anticipation of daily environmental change. To assess the robustness of a human molecular clock, we systematically depleted known clock components and observed that circadian oscillations are maintained over a wide range of disruptions. We developed a novel strategy termed Gene Dosage Network Analysis (GDNA) in which small interfering RNA (siRNA)-induced dose-dependent changes in gene expression were used to build gene association networks consistent with known biochemical constraints. The use of multiple doses powered the analysis to uncover several novel network features of the circadian clock, including proportional responses and signal propagation through interacting genetic modules. We also observed several examples where a gene is up-regulated following knockdown of its paralog, suggesting the clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function. We propose that these network features act in concert as a genetic buffering system to maintain clock function in the face of genetic and environmental perturbation