Nitrogen depletion in the fission yeast Schizosaccharomyces pombe causes nucleosome loss

Gene transcription is associated with local changes in chromatin, both in nucleosome positions and in chemical modifications of the histones. Chromatin dynamics has mostly been studied on a single-gene basis. Those genome-wide studies that have been made primarily investigated steady-state transcription. However, three studies of genome-wide changes in chromatin during the transcriptional response to heat shock in the budding yeast Saccharomyces cerevisiae revealed nucleosome eviction in promoter regions but only minor effects in coding regions. Here, we describe the short-term response to nitrogen starvation in the fission yeast Schizosaccharomyces pombe. Nitrogen depletion leads to a fast induction of a large number of genes in S. pombe and is thus suitable for genome-wide studies of chromatin dynamics during gene regulation.

After 20 min of nitrogen removal, 118 transcripts were up-regulated. The distribution of regulated genes throughout the genome was not random; many up-regulated genes were found in clusters, while large parts of the genome were devoid of up-regulated genes. Surprisingly, this up-regulation was associated with nucleosome eviction of equal magnitudes in the promoters and in the coding regions. The nucleosome loss was not limited to induction by nitrogen depletion but also occurred during cadmium treatment. Furthermore, the lower nucleosome density persisted for at least 60 min after induction. Two highly induced genes,urg1+ and urg2+, displayed a substantial nucleosome loss, with only 20% of the nucleosomes being left in the coding region. We conclude that nucleosome loss during transcriptional activation is not necessarily limited to promoter regions. Review the abstract or order this article via the Genome Research portal

Regulation of Energy Homeostasis by Bombesin Receptor Subtype-3 (Cell Metabolism)

Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake and body weight, whereas agonists increased metabolic rate and reduced food intake and body weight. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis.

BRS-3 agonist effectiveness was absent in Brs3^-/Y (BRS-3 null) mice but was maintained in Npy^-/-Agrp^-/-, Mc4r^-/-, Cnr1^-/-, and Lepr^db/db mice. In addition, Brs3^-/Y mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. These results demonstrate that BRS-3 has a role in energy homeostasis that complements several well-known pathways and that BRS-3 agonists represent a potential approach to the treatment of obesity. Review the article and join the discussion via the Cell Metabolism portal

TGen finalizes alliance with Van Andel Research Institute (VARI)

The Translational Genomics Research Institute (TGen) announced the completion of a strategic alliance and affiliation agreement with the Van Andel Research Institute (VARI) that will maximize the research capabilities of both non-profit institutes. TGen expects the agreement to create a robust basic-science-to-translational delivery platform aimed at developing new tests and treatments for patient benefit.

"We are excited to align with a prominent institute like Van Andel, a partnership that I fully expect to yield greater scientific and economic returns for both Arizona and Michigan," said Dr. Jeffrey Trent, TGen's President and Research Director, a title he also now holds at VARI.

TGen remains an Arizona-based 501(c)(3) non-profit biomedical research organization, headquartered in Phoenix with an Arizona-centric board. VARI, based in Grand Rapids, Michigan, will be the organization's sole member. Since making an initial alliance announcement in February 2009, TGen worked with key Arizona partners to ratify any needed changes to funding or research agreements, including the Flinn Foundation, the Virginia G. Piper Charitable Trust, the Arizona Board of Regents, a number of the Valley's health care providers, and the State of Arizona. Visit the TGen news room for complete partnership details

Positioned and G/C capped poly(dA:dT) tracts associate with the centers of nucleosome-free regions

Eukaryotic transcriptional regulation is mediated by the organization of nucleosomes in promoter regions. Most S. cerevisiae promoters have a highly stereotyped chromatin organization, where nucleosome-free regions (NFR) are flanked by well-ordered nucleosomes. We have found that yeast promoters fall into two classes differing in NFR sharpness, and that this distinction follows a known transcriptional dichotomy in yeast genes. A class of yeast promoters having well-defined NFRs are characterized by positioned patterns of poly(dA:dT) tracts with several novel features. First, poly(dA:dT) tracts are localized in a strand-dependent manner, with poly(dA) tracts lying proximal to transcriptional start sites and poly(dT) tracts lying distal, and collectively define a symmetry axis that is coincident with NFR centers.

Second, poly(dA:dT) tracts are preferentially "capped" by G:C residues on the terminus proximal to the symmetry axis. Both signature features co-vary with fine positional variations between NFRs, establishing a closely-knit relationship between poly(dA:dT) tracts, their capping patterns, and the central coordinates of NFRs. We found that these features are unique to promoters with well-defined NFRs, and that these promoters display significant difference between in vitro and in vivo nucleosome occupancy patterns. These observations are consistent with a model in which localized and G:C-capped poly(dA:dT) tracts initiate or facilitate the formation of NFRs at their center, possibly with chromatin remodeling and transcriptional machines involved.

Network-Based Elucidation of Human Disease Similarities Reveals Common Functional Modules Enriched for Pluripotent Drug Targets (PLoS)

Many human diseases are related to each other through shared causes or even shared pathology. Knowledge of these relationships has long been exploited to treat similar diseases with the same therapies. However, most of the traditional approaches to discover these relationships have depended on subjective measures, such as similarity in symptoms, or incomplete knowledge, such as genes with mutations. Here we present the first approach integrating high-throughput datasets such as mRNA expression and large-scale protein-protein interaction networks to discover human disease relationships in a systematic and quantitative way. We discover 138 significant pathological similarities between 54 human diseases ranging from lung cancer, schizophrenia, and malaria.

We also discovered a set of common pathways and processes within the cell that are dysregulated in at least half of the diseases. We infer that these processes correspond to a common response of the human system to a disease state. Interestingly, we find that many of the proteins in these pathways are already known to be targets of existing drugs. In fact, the drugs corresponding to these proteins are known to treat significantly more diseases than expected by chance highlighting the importance of these common molecular pathological pathways as prime therapeutic opportunities. Review the complete abstract or order this report via the PLoS portal