Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas

Past, present and future of chamois science

The chamois Rupicapra spp. is the most abundant mountain ungulate of Europe and the Near East, where it occurs as two spe- cies, the northern chamois R. rupicapra and the southern chamois R. pyrenaica. Here, we provide a state-of-the-art overview of research trends and the most challenging issues in chamois research and conservation, focusing on taxonomy and systematics, genetics, life history, ecology and behavior, physiology and disease, management and conservation. Research on Rupicapra has a longstanding history and has contributed substantially to the biological and ecological knowledge of mountain ungulates. Although the number of publications on this genus has markedly increased over the past two decades, major differences persist with respect to knowledge of species and subspecies, with research mostly focusing on the Alpine chamois R. r. rupicapra and, to a lesser extent, the Pyrenean chamois R. p. pyrenaica. In addition, a scarcity of replicate studies of populations of different subspecies and/or geographic areas limits the advancement of chamois science. Since environmental heterogeneity impacts behavioral, physiological and life history traits, understanding the underlying processes would be of great value from both an evolutionary and conservation/management standpoint, especially in the light of ongoing climatic change. Substantial contri- butions to this challenge may derive from a quantitative assessment of reproductive success, investigation of fine-scale foraging patterns, and a mechanistic understanding of disease outbreak and resilience. For improving conservation status, resolving taxonomic disputes, identifying subspecies hybridization, assessing the impact of hunting and establishing reliable methods of abundance estimation are of primary concern. Despite being one of the most well-known mountain ungulates, substantial field efforts to collect paleontological, behavioral, ecological, morphological, physiological and genetic data on different popu- lations and subspecies are still needed to ensure a successful future for chamois research and conservation

Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity

A better understanding of the mechanisms underlying neuronal death in cerebral ischemia is required for the development of stroke therapies. Here we analyze the contribution of the tropomyosin-related kinase B (TrkB) neurotrophin receptor to excitotoxicity, a primary pathological mechanism in ischemia, which is induced by overstimulation of glutamate receptors of the N-methyl-D-aspartate type. We demonstrate a significant modification of TrkB expression that is strongly associated with neurodegeneration in models of ischemia and in vitro excitotoxicity. Two mechanisms cooperate for TrkB dysregulation: (1) calpain-processing of full-length TrkB (TrkB-FL), high-affinity receptor for brain-derived neurotrophic factor, which produces a truncated protein lacking the tyrosine-kinase domain and strikingly similar to the inactive TrkB-T1 isoform and (2) reverse regulation of the mRNA of these isoforms. Collectively, excitotoxicity results in a decrease of TrkB-FL, the production of truncated TrkB-FL and the upregulation of TrkB-T1. A similar neuro-specific increase of the TrkB-T1 isoform is also observed in stroke patients. A lentivirus designed for both neuro-specific TrkB-T1 interference and increased TrkB-FL expression allows recovery of the TrkB-FL/TrkB-T1 balance and protects neurons from excitotoxic death. These data implicate a combination of TrkB-FL downregulation and TrkB-T1 upregulation as significant causes of neuronal death in excitotoxicity, and reveal novel targets for the design of stroke therapies

UVA and UVB formulation phototoxicity in a three-dimensional human skin model: photodegradation effect

In vitro three-dimensional human skin models are an innovative alternative to evaluate cytotoxicity and phototoxicity in the cosmetic industry. The aim of this study was to use a skin model to evaluate the potential toxicity of sunscreen formulations with or without exposure to UV radiation. In addition, the toxicity of these formulations was evaluated after exposure to photodegradation. The results showed toxicity with all formulations/conditions tested, including the control formulation, compared to PBS. Cell viability of photodegraded formulations - prior to the phototoxicity radiation process - was higher, indicating that some formulation components were degraded into products with reduced toxicity. The results also indicated that avobenzone was more unstable/toxic than octyl p-methoxycinnamate under the same test conditions. The sunscreens and their formulations were shown to be toxic to skin model cells to some extent, even when not exposed to UV irradiation; however the biological role of this toxicity is unclear. This result shows the importance of testing sunscreen formulations in real in-use conditions. Finally, since we used an in vitro assay based on a human cell model, this non-invasive technique represents a suitable alternative to animal models for phototoxicity tests in general and could have application in screening new sunscreen products

Preventing seismic pounding of adjacent structures using viscous wall damper device

Today, a number of researchers are broadly studying the effective implementation of supplemental seismic energy dissipation systems to improve seismic behavior of structures during earthquakes. The current article studies the impacts of employing Viscous Wall Damper devices to couple two adjacent structures on seismic response of the new system. An exclusive finite element algorithm capable of modeling and analyzing structures equipped with special damper systems was used in order to perform a nonlinear time history analysis subjected to seismic excitation. Two ten-story RC framed structures are modeled adjacently in 11 different cases, each representing existence or damping coefficient of the Viscous Wall Damper device. A parametric study has been conducted in each case to assess the effectiveness of implementing Viscous Wall Damper devices on improving seismic behavior of the coupled structure. The considered metrics include rotation and displacement amplitude, plastic hinge formation, and induced element forces. It has been proved that the proposed damper system substantially diminishes and dissipates induced seismic response of the system. Also, it is indicated that the extent to which Viscous Wall Damper device contributes in mitigating seismic responses is highly correlated with the damping coefficient

Psip1/Ledgf p52 Binds Methylated Histone H3K36 and Splicing Factors and Contributes to the Regulation of Alternative Splicing

Increasing evidence suggests that chromatin modifications have important roles in modulating constitutive or alternative splicing. Here we demonstrate that the PWWP domain of the chromatin-associated protein Psip1/Ledgf can specifically recognize tri-methylated H3K36 and that, like this histone modification, the Psip1 short (p52) isoform is enriched at active genes. We show that the p52, but not the long (p75), isoform of Psip1 co-localizes and interacts with Srsf1 and other proteins involved in mRNA processing. The level of H3K36me3 associated Srsf1 is reduced in Psip1 mutant cells and alternative splicing of specific genes is affected. Moreover, we show altered Srsf1 distribution around the alternatively spliced exons of these genes in Psip1 null cells. We propose that Psip1/p52, through its binding to both chromatin and splicing factors, might act to modulate splicing

The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair factors and R-loop processing

Recent whole-exome sequencing of malignancies have detected recurrent somatic mutations in U2 small nuclear ribonucleoprotein complex (snRNP) components of the spliceosome. These factors have also been identified as novel players in the DNA-damage response (DDR) in several genome-wide screens and proteomic analysis. Although accumulating evidence implies that the spliceosome has an important role in genome stability and is an emerging hallmark of cancer, its precise role in DNA repair still remains elusive. Here we identify two distinct mechanisms of how spliceosome U2 snRNP factors contribute to genome stability. We show that the spliceosome maintains protein levels of essential repair factors, thus contributing to homologous recombination repair. In addition, real-time laser microirradiation analysis identified rapid recruitment of the U2 snRNP factor SNRPA1 to DNA-damage sites. Functional analysis of SNRPA1 revealed a more immediate and direct role in preventing R-loop-induced DNA damage. Our present study implies a complex interrelation between transcription, mRNA splicing and the DDR. Cells require rapid spatio-temporal coordination of these chromatin transactions to cope with various forms of genotoxic stress