Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression

Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute normalization unmasks global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulates transcriptional changes seen with triplication of a Down syndrome critical region on distal chromosome 21, and HMGN1 is necessary for B cell phenotypes in DS models. Absolute exogenous-normalized chromatin immunoprecipitation sequencing (ChIP-Rx) also reveals a global increase in histone H3K27 acetylation caused by HMGN1. Transcriptional amplification downstream of HMGN1 is enriched for stage-specific programs of B cells and B cell acute lymphoblastic leukemia, dependent on the developmental cellular context. These data offer a mechanistic explanation for DS transcriptional patterns and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted. How trisomy 21 contributes to Down syndrome phenotypes, including increased leukemia risk, is not well understood. Mowery et al. use per-cell normalization approaches to reveal global transcriptional amplification in Down syndrome models. HMGN1 overexpression is sufficient to induce these alterations and promotes lineage-associated transcriptional programs, signaling, and B cell progenitor phenotypes

Structural plasticity of single chromatin fibers revealed by torsional manipulation

Magnetic tweezers are used to study the mechanical response under torsion of single nucleosome arrays reconstituted on tandem repeats of 5S positioning sequences. Regular arrays are extremely resilient and can reversibly accommodate a large amount of supercoiling without much change in length. This behavior is quantitatively described by a molecular model of the chromatin 3-D architecture. In this model, we assume the existence of a dynamic equilibrium between three conformations of the nucleosome, which are determined by the crossing status of the entry/exit DNAs (positive, null or negative). Torsional strain, in displacing that equilibrium, extensively reorganizes the fiber architecture. The model explains a number of long-standing topological questions regarding DNA in chromatin, and may provide the ground to better understand the dynamic binding of most chromatin-associated proteins.Comment: 18 pages, 7 figures, Supplementary information available at http://www.nature.com/nsmb/journal/v13/n5/suppinfo/nsmb1087_S1.htm

One ligand, two regulators and three binding sites: How KDPG controls primary carbon metabolism in Pseudomonas

Effective regulation of primary carbon metabolism is critically important for bacteria to successfully adapt to different environments. We have identified an uncharacterised transcriptional regulator; RccR, that controls this process in response to carbon source availability. Disruption of rccR in the plant-associated microbe Pseudomonas fluorescens inhibits growth in defined media, and compromises its ability to colonise the wheat rhizosphere. Structurally, RccR is almost identical to the Entner-Doudoroff (ED) pathway regulator HexR, and both proteins are controlled by the same ED-intermediate; 2-keto-3-deoxy-6-phosphogluconate (KDPG). Despite these similarities, HexR and RccR control entirely different aspects of primary metabolism, with RccR regulating pyruvate metabolism (aceEF), the glyoxylate shunt (aceA, glcB, pntAA) and gluconeogenesis (pckA, gap). RccR displays complex and unusual regulatory behaviour; switching repression between the pyruvate metabolism and glyoxylate shunt/gluconeogenesis loci depending on the available carbon source. This regulatory complexity is enabled by two distinct pseudo-palindromic binding sites, differing only in the length of their linker regions, with KDPG binding increasing affinity for the 28 bp aceA binding site but decreasing affinity for the 15 bp aceE site. Thus, RccR is able to simultaneously suppress and activate gene expression in response to carbon source availability. Together, the RccR and HexR regulators enable the rapid coordination of multiple aspects of primary carbon metabolism, in response to levels of a single key intermediate

Effect of Grit Size on Airborne Particle Concentration and Size Distribution during Oak Wood Sanding

Adverse health effects caused by exposure to airborne particles have been detected in recent years, however there is little knowledge about exposure to ultrafine particles with a diameter <100 nm. In this study, particle number concentration and size distribution in a range of particle diameters from 10 nm to 10 µm were determined during oak wood sanding. A hand-held orbit sander in combination with three types of grit size (P60, 120 and 240) of sandpaper were used. Measurements were obtained using a portable particle size distribution analyzer and an optical particle size spectrometer, carried out at 15-min intervals for each treatment by static sampling in the breathing zone. We also compared the optical particle size spectrometer to the aerosol monitor in order to evaluate the mass concentration of airborne particles in the range of 1 to 10 µm in diameter. Sanding paper with the finest grit, P240, showed a significantly higher number concentration of ultrafine particles, compared with P60 and P120 grits. The differences among particular grit size were statistically significant for microparticles. The size distribution of particles during sanding was not affected by grit size. For each grit size, apparent peak values of ultrafine and microparticle number concentrations were determined at approximately 15 nm, and 0.1 µm, respectively. Optical particle size spectrometer and aerosol monitor showed comparable results of mass concentration for the respirable fraction

Solutions for the size & concentration measurement of aerosols from combustion

Currently the main pollution comes from the anthropogenic sources related to residential heating and combustion. Most of the emitted particles from this sources are in the mode below 1 μm. Therefore, only by using methods based on the electric mobility separation and size enhancement we can measure the size and concentration of this particles from nano to ultrafine sizes. This contribution describes the most recent methods how to study particle size and concentration of the particles coming from combustion sources

Solutions for the size & concentration measurement of aerosols from combustion

Currently the main pollution comes from the anthropogenic sources related to residential heating and combustion. Most of the emitted particles from this sources are in the mode below 1 μm. Therefore, only by using methods based on the electric mobility separation and size enhancement we can measure the size and concentration of this particles from nano to ultrafine sizes. This contribution describes the most recent methods how to study particle size and concentration of the particles coming from combustion sources