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

Low sequence diversity of the prion protein gene (PRNP) in wild deer and goat species from Spain

Abstract The first European cases of chronic wasting disease (CWD) in free-ranging reindeer and wild elk were confirmed in Norway in 2016 highlighting the urgent need to understand transmissible spongiform encephalopathies (TSEs) in the context of European deer species and the many individual populations throughout the European continent. The genetics of the prion protein gene (PRNP) are crucial in determining the relative susceptibility to TSEs. To establish PRNP gene sequence diversity for free-ranging ruminants in the Northeast of Spain, the open reading frame was sequenced in over 350 samples from five species: Iberian red deer (Cervus elaphus hispanicus), roe deer (Capreolus capreolus), fallow deer (Dama dama), Iberian wild goat (Capra pyrenaica hispanica) and Pyrenean chamois (Rupicapra p. pyrenaica). Three single nucleotide polymorphisms (SNPs) were found in red deer: a silent mutation at codon 136, and amino acid changes T98A and Q226E. Pyrenean chamois revealed a silent SNP at codon 38 and an allele with a single octapeptide-repeat deletion. No polymorphisms were found in roe deer, fallow deer and Iberian wild goat. This apparently low variability of the PRNP coding region sequences of four major species in Spain resembles previous findings for wild mammals, but implies that larger surveys will be necessary to find novel, low frequency PRNP gene alleles that may be utilized in CWD risk control

Interplay between estrogen receptor and AKT in estradiol-induced alternative splicing.

BACKGROUND: Alternative splicing is critical for generating complex proteomes in response to extracellular signals. Nuclear receptors including estrogen receptor alpha (ERα) and their ligands promote alternative splicing. The endogenous targets of ERα:estradiol (E2)-mediated alternative splicing and the influence of extracellular kinases that phosphorylate ERα on E2-induced splicing are unknown. METHODS: MCF-7 and its anti-estrogen derivatives were used for the majority of the assays. CD44 mini gene was used to measure the effect of E2 and AKT on alternative splicing. ExonHit array analysis was performed to identify E2 and AKT-regulated endogenous alternatively spliced apoptosis-related genes. Quantitative reverse transcription polymerase chain reaction was performed to verify alternative splicing. ERα binding to alternatively spliced genes was verified by chromatin immunoprecipitation assay. Bromodeoxyuridine incorporation-ELISA and Annexin V labeling assays were done to measure cell proliferation and apoptosis, respectively. RESULTS: We identified the targets of E2-induced alternative splicing and deconstructed some of the mechanisms surrounding E2-induced splicing by combining splice array with ERα cistrome and gene expression array. E2-induced alternatively spliced genes fall into at least two subgroups: coupled to E2-regulated transcription and ERα binding to the gene without an effect on rate of transcription. Further, AKT, which phosphorylates both ERα and splicing factors, influenced ERα:E2 dependent splicing in a gene-specific manner. Genes that are alternatively spliced include FAS/CD95, FGFR2, and AXIN-1. E2 increased the expression of FGFR2 C1 isoform but reduced C3 isoform at mRNA level. E2-induced alternative splicing of FAS and FGFR2 in MCF-7 cells correlated with resistance to FAS activation-induced apoptosis and response to keratinocyte growth factor (KGF), respectively. Resistance of MCF-7 breast cancer cells to the anti-estrogen tamoxifen was associated with ERα-dependent overexpression of FGFR2, whereas resistance to fulvestrant was associated with ERα-dependent isoform switching, which correlated with altered response to KGF. CONCLUSION: E2 may partly alter cellular proteome through alternative splicing uncoupled to its effects on transcription initiation and aberration in E2-induced alternative splicing events may influence response to anti-estrogens.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Enfermedades crónicas

Adherencia al tratamiento farmacológico y relación con el control metabólico en pacientes con DM2Aluminio en pacientes con terapia de reemplazo renal crónico con hemodiálisis en Bogotá, ColombiaAmputación de extremidades inferiores: ¿están aumentando las tasas?Consumo de edulcorantes artificiales en jóvenes universitariosCómo crecen niños normales de 2 años que son sobrepeso a los 7 añosDiagnóstico con enfoque territorial de salud cardiovascular en la Región MetropolitanaEfecto a corto plazo de una intervención con ejercicio físico, en niños con sobrepesoEfectos de la cirugía bariátrica en pacientes con síndrome metabólico e IMC < 35 KG/M2Encuesta mundial de tabaquismo en estudiantes de profesiones de saludEnfermedades crónicas no transmisibles: Consecuencias sociales-sanitarias de comunidades rurales en ChileEpidemiología de las muertes hospitalarias por patologías relacionadas a muerte encefálica, Chile 2003-2007Estado nutricional y conductas alimentarias en adolescentes de 4º medio de la Región de CoquimboEstudio de calidad de vida en una muestra del plan piloto para hepatitis CEvaluación del proceso asistencial y de resultados de salud del GES de diabetes mellitus 2Factores de riesgo cardiovascular en población universitaria de la Facsal, universidad de TarapacáImplicancias psicosociales en la génesis, evolución y tratamiento de pacientes con hipertensión arterial esencialInfarto agudo al miocardio (IAM): Realidad en el Hospital de Puerto Natales, 2009-2010Introducción de nuevas TIC y mejoría de la asistencia a un programa de saludNiños obesos atendidos en el Cesfam de Puerto Natales y su entorno familiarPerfil de la mortalidad por cáncer de cuello uterino en Río de JaneiroPerfil del paciente primo-consultante del Programa de Salud Cardiovascular, Consultorio Cordillera Andina, Los AndesPrevalencia de automedicación en mujeres beneficiarias del Hospital Comunitario de Til-TiPrevalencia de caries en población preescolar y su relación con malnutrición por excesoPrevalencia de retinopatía diabética en comunas dependientes del Servicio de Salud Metropolitano Occidente (SSMOC)Problemas de adherencia farmacológica antihipertensiva en población mapuche: Un estudio cualitativoRol biológico de los antioxidantes innatos en pacientes portadores de VIH/SidaSobrepeso en empleados de un restaurante de una universidad pública del estado de São Paul

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

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

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

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