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Mularoni L.,University Pompeu Fabra | Mularoni L.,Barcelona Institute for Research in Biomedicine | Ramos-Rodriguez M.,Germans Trias i Pujol University Hospital and Research Institute | Pasquali L.,Germans Trias i Pujol University Hospital and Research Institute | And 2 more authors.
Frontiers in Genetics | Year: 2017

The pancreatic islet is a highly specialized tissue embedded in the exocrine pancreas whose primary function is that of controlling glucose homeostasis. Thus, understanding the transcriptional control of islet-cell may help to puzzle out the pathogenesis of glucose metabolism disorders. Integrative computational analyses of transcriptomic and epigenomic data allows predicting genomic coordinates of putative regulatory elements across the genome and, decipher tissue-specific functions of the non-coding genome. We herein present the Islet Regulome Browser, a tool that allows fast access and exploration of pancreatic islet epigenomic and transcriptomic data produced by different labs worldwide. The Islet Regulome Browser is now accessible on the internet or may be installed locally. It allows uploading custom tracks as well as providing interactive access to a wealth of information including Genome-Wide Association Studies (GWAS) variants, different classes of regulatory elements, together with enhancer clusters, stretch-enhancers and transcription factor binding sites in pancreatic progenitors and adult human pancreatic islets. Integration and visualization of such data may allow a deeper understanding of the regulatory networks driving tissue-specific transcription and guide the identification of regulatory variants. We believe that such tool will facilitate the access to pancreatic islet public genomic datasets providing a major boost to functional genomics studies in glucose metabolism related traits including diabetes. © 2017 Mularoni, Ramos-Rodríguez and Pasquali.


Capilla L.,Autonomous University of Barcelona | Sanchez-Guillen R.A.,Autonomous University of Barcelona | Sanchez-Guillen R.A.,Institute Ecologia Ac | Farre M.,Royal Veterinary College | And 6 more authors.
Genome Biology and Evolution | Year: 2016

Understanding how mammalian genomes have been reshuffled through structural changes is fundamental to the dynamics of its composition, evolutionary relationships between species and, in the long run, speciation. In this work, we reveal the evolutionary genomic landscape in Rodentia, the most diverse and speciose mammalian order, by whole-genome comparisons of six rodent species and six representative outgroupmammalian species. The reconstruction of the evolutionary breakpoint regions across rodent phylogeny shows an increased rate of genome reshuffling that is approximately two orders of magnitude greater than in other mammalian species here considered.We identified novel lineage and clade-specific breakpoint regions within Rodentia and analyzed their gene content, recombination rates and their relationship with constitutive lamina genomic associated domains, DNase I hypersensitivity sites and chromatin modifications. We detected an accumulation of protein-coding genes in evolutionary breakpoint regions, especiallygenes implicated in reproductionandpheromonedetectionandmating.Moreover,wefoundanassociationof the evolutionary breakpoint regions with active chromatin state landscapes, most probably related to gene enrichment. Our results have two important implications for understanding themechanisms that govern and constrainmammalian genome evolution. The first is that the presence of genes related to species-specific phenotypes in evolutionary breakpoint regions reinforces the adaptive value of genome reshuffling. Second, that chromatin conformation, an aspect that has been often overlooked in comparative genomic studies, might play a role in modeling the genomic distribution of evolutionary breakpoints. © The Author 2016.


Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous neoplasia with poor outcome, organized as a hierarchy initiated and maintained by a sub-population with differentiation and self-renewal capacities called leukemia stem cells (LSCs). Although currently used chemotherapy is capable of initially reducing the tumor burden producing a complete remission, most patients will ultimately relapse and will succumb to their disease. As such, new therapeutic strategies are needed. AML cells differentially expressed serotonin receptor type 1 (HTR1) compared with healthy blood cells and the most primitive hematopoietic fraction; in fact, HTR1B expression on AML patient samples correlated with clinical outcome. Inhibition of HTR1s activated the apoptosis program, induced differentiation and reduced the clonogenic capacity, while minimal effect was observed on healthy blood cells. In vivo regeneration capacity of primary AML samples was disrupted upon inhibition of HTR1. The self-renewal capacity remaining in AML cells upon in vivo treatment was severely reduced as demonstrated by serial transplantation. Thus, treatment with HTR1 antagonists showed antileukemia effect, especially anti-LSC activity while sparing healthy blood cells. Our results highlight the importance of HTR1 in leukemogenesis and LSC survival and identify this receptor family as a new target for therapy in AML with prognostic value.Leukemia advance online publication, 10 March 2017; doi:10.1038/leu.2017.52. © 2017 Macmillan Publishers Limited, part of Springer Nature.


News Article | April 20, 2017
Site: www.eurekalert.org

CRG scientists have discovered that the impact of environmental change can be passed on in the genes of tiny nematode worms for at least 14 generations -- the most that has ever been seen in animals Led by Dr Ben Lehner, group leader at the EMBL-CRG Systems Biology Unit and ICREA and AXA Professor, together with Dr Tanya Vavouri from the Josep Carreras Leukaemia Research Institute and the Institute for Health Science Research Germans Trias i Pujol (IGTP), the researchers noticed that the impact of environmental change can be passed on in the genes for many generations while studying C. elegans worms carrying a transgene array - a long string of repeated copies of a gene for a fluorescent protein that had been added into the worm genome using genetic engineering techniques. If the worms were kept at 20 degrees Celsius, the array of transgenes was less active, creating only a small amount of fluorescent protein. But shifting the animals to a warmer climate of 25 degrees significantly increased the activity of the transgenes, making the animals glow brightly under ultraviolet light when viewed down a microscope. When these worms were moved back to the cooler temperature, their transgenes were still highly active, suggesting they were somehow retaining the 'memory' of their exposure to warmth. Intriguingly, this high activity level was passed on to their offspring and onwards for 7 subsequent generations kept solely at 20 degrees, even though the original animals only experienced the higher temperature for a brief time. Keeping worms at 25 degrees for five generations led to the increased transgene activity being maintained for at least 14 generations once the animals were returned to cooler conditions. Although this phenomenon has been seen in a range of animal species - including fruit flies, worms and mammals including humans - it tends to fade after a few generations. These findings, which will be published on Friday 21st April in the journal Science, represent the longest maintenance of transgenerational environmental 'memory' ever observed in animals to date. "We discovered this phenomenon by chance, but it shows that it's certainly possible to transmit information about the environment down the generations," says Lehner. "We don't know exactly why this happens, but it might be a form of biological forward-planning," adds the first author of the study and CRG Alumnus, Adam Klosin. "Worms are very short-lived, so perhaps they are transmitting memories of past conditions to help their descendants predict what their environment might be like in the future," adds Vavouri. Comparing the transgenes that were less active with those that had become activated by the higher temperature, Lehner and his team discovered crucial differences in a type of molecular 'tag' attached to the proteins packaging up the genes, known as histone methylation.* Transgenes in animals that had only ever been kept at 20 degrees had high levels of histone methylation, which is associated with silenced genes, while those that had been moved to 25 degrees had largely lost the methylation tags. Importantly, they still maintained this reduced histone methylation when moved back to the cooler temperature, suggesting that it is playing an important role in locking the memory into the transgenes.** The researchers also found that repetitive parts of the normal worm genome that look similar to transgene arrays also behave in the same way, suggesting that this is a widespread memory mechanism and not just restricted to artificially engineered genes.


News Article | April 20, 2017
Site: www.chromatographytechniques.com

Scientists at the Centre for Genomic Regulation (CRG) in Barcelona and the Josep Carreras Leukaemia Research Institute and The Institute for Health Science Research Germans Trias i Pujol (IGTP) in Badalona, Spain, have discovered that the impact of environmental change can be passed on in the genes of tiny nematode worms for at least 14 generations—the most that has ever been seen in animals. The findings will be published on Friday, April 21, in the journal Science. Led by Ben Lehner, group leader at the EMBL-CRG Systems Biology Unit and ICREA and AXA professor, together with Tanya Vavouri from the Josep Carreras Leukaemia Research Institute and the Institute for Health Science Research Germans Trias i Pujol (IGTP), the researchers noticed that the impact of environmental change can be passed on in the genes for many generations while studying C. elegans worms carrying a transgene array -- a long string of repeated copies of a gene for a fluorescent protein that had been added into the worm genome using genetic engineering techniques. If the worms were kept at 20 degrees Celsius, the array of transgenes was less active, creating only a small amount of fluorescent protein. But shifting the animals to a warmer climate of 25 degrees significantly increased the activity of the transgenes, making the animals glow brightly under ultraviolet light when viewed down a microscope. When these worms were moved back to the cooler temperature, their transgenes were still highly active, suggesting they were somehow retaining the "memory" of their exposure to warmth. Intriguingly, this high activity level was passed on to their offspring and onwards for seven subsequent generations kept solely at 20 degrees, even though the original animals only experienced the higher temperature for a brief time. Keeping worms at 25 degrees for five generations led to the increased transgene activity being maintained for at least 14 generations once the animals were returned to cooler conditions. Although this phenomenon has been seen in a range of animal species - including fruit flies, worms and mammals including humans - it tends to fade after a few generations. These findings represent the longest maintenance of transgenerational environmental "memory" ever observed in animals to date. "We discovered this phenomenon by chance, but it shows that it's certainly possible to transmit information about the environment down the generations," says Lehner. "We don't know exactly why this happens, but it might be a form of biological forward-planning," adds first author of the study and CRG Alumnus, Adam Klosin. "Worms are very short-lived, so perhaps they are transmitting memories of past conditions to help their descendants predict what their environment might be like in the future," adds Vavouri. Comparing the transgenes that were less active with those that had become activated by the higher temperature, Lehner and his team discovered crucial differences in a type of molecular "tag" attached to the proteins packaging up the genes, known as histone methylation. Transgenes in animals that had only ever been kept at 20 degrees had high levels of histone methylation, which is associated with silenced genes, while those that had been moved to 25 degrees had largely lost the methylation tags. Importantly, they still maintained this reduced histone methylation when moved back to the cooler temperature, suggesting that it is playing an important role in locking the memory into the transgenes. The researchers also found that repetitive parts of the normal worm genome that look similar to transgene arrays also behave in the same way, suggesting that this is a widespread memory mechanism and not just restricted to artificially engineered genes.


News Article | April 20, 2017
Site: www.chromatographytechniques.com

Scientists at the Centre for Genomic Regulation (CRG) in Barcelona and the Josep Carreras Leukaemia Research Institute and The Institute for Health Science Research Germans Trias i Pujol (IGTP) in Badalona, Spain, have discovered that the impact of environmental change can be passed on in the genes of tiny nematode worms for at least 14 generations—the most that has ever been seen in animals. The findings will be published on Friday, April 21, in the journal Science. Led by Ben Lehner, group leader at the EMBL-CRG Systems Biology Unit and ICREA and AXA professor, together with Tanya Vavouri from the Josep Carreras Leukaemia Research Institute and the Institute for Health Science Research Germans Trias i Pujol (IGTP), the researchers noticed that the impact of environmental change can be passed on in the genes for many generations while studying C. elegans worms carrying a transgene array -- a long string of repeated copies of a gene for a fluorescent protein that had been added into the worm genome using genetic engineering techniques. If the worms were kept at 20 degrees Celsius, the array of transgenes was less active, creating only a small amount of fluorescent protein. But shifting the animals to a warmer climate of 25 degrees significantly increased the activity of the transgenes, making the animals glow brightly under ultraviolet light when viewed down a microscope. When these worms were moved back to the cooler temperature, their transgenes were still highly active, suggesting they were somehow retaining the "memory" of their exposure to warmth. Intriguingly, this high activity level was passed on to their offspring and onwards for seven subsequent generations kept solely at 20 degrees, even though the original animals only experienced the higher temperature for a brief time. Keeping worms at 25 degrees for five generations led to the increased transgene activity being maintained for at least 14 generations once the animals were returned to cooler conditions. Although this phenomenon has been seen in a range of animal species - including fruit flies, worms and mammals including humans - it tends to fade after a few generations. These findings represent the longest maintenance of transgenerational environmental "memory" ever observed in animals to date. "We discovered this phenomenon by chance, but it shows that it's certainly possible to transmit information about the environment down the generations," says Lehner. "We don't know exactly why this happens, but it might be a form of biological forward-planning," adds first author of the study and CRG Alumnus, Adam Klosin. "Worms are very short-lived, so perhaps they are transmitting memories of past conditions to help their descendants predict what their environment might be like in the future," adds Vavouri. Comparing the transgenes that were less active with those that had become activated by the higher temperature, Lehner and his team discovered crucial differences in a type of molecular "tag" attached to the proteins packaging up the genes, known as histone methylation. Transgenes in animals that had only ever been kept at 20 degrees had high levels of histone methylation, which is associated with silenced genes, while those that had been moved to 25 degrees had largely lost the methylation tags. Importantly, they still maintained this reduced histone methylation when moved back to the cooler temperature, suggesting that it is playing an important role in locking the memory into the transgenes. The researchers also found that repetitive parts of the normal worm genome that look similar to transgene arrays also behave in the same way, suggesting that this is a widespread memory mechanism and not just restricted to artificially engineered genes.


News Article | April 20, 2017
Site: phys.org

Scientists at the Centre for Genomic Regulation (CRG) in Barcelona and the Josep Carreras Leukaemia Research Institute and The Institute for Health Science Research Germans Trias i Pujol (IGTP) in Badalona, Spain, have discovered that the impact of environmental change can be passed on in the genes of tiny nematode worms for at least 14 generations—the most that has ever been seen in animals. The findings will be published on Friday, April 21, in the journal Science. Led by Dr Ben Lehner, group leader at the EMBL-CRG Systems Biology Unit and ICREA and AXA Professor, together with Dr Tanya Vavouri from the Josep Carreras Leukaemia Research Institute and the Institute for Health Science Research Germans Trias i Pujol (IGTP), the researchers noticed that the impact of environmental change can be passed on in the genes for many generations while studying C. elegans worms carrying a transgene array - a long string of repeated copies of a gene for a fluorescent protein that had been added into the worm genome using genetic engineering techniques. If the worms were kept at 20 degrees Celsius, the array of transgenes was less active, creating only a small amount of fluorescent protein. But shifting the animals to a warmer climate of 25 degrees significantly increased the activity of the transgenes, making the animals glow brightly under ultraviolet light when viewed down a microscope. When these worms were moved back to the cooler temperature, their transgenes were still highly active, suggesting they were somehow retaining the 'memory' of their exposure to warmth. Intriguingly, this high activity level was passed on to their offspring and onwards for 7 subsequent generations kept solely at 20 degrees, even though the original animals only experienced the higher temperature for a brief time. Keeping worms at 25 degrees for five generations led to the increased transgene activity being maintained for at least 14 generations once the animals were returned to cooler conditions. Although this phenomenon has been seen in a range of animal species - including fruit flies, worms and mammals including humans - it tends to fade after a few generations. These findings, which will be published on Friday 21st April in the journal Science, represent the longest maintenance of transgenerational environmental 'memory' ever observed in animals to date. "We discovered this phenomenon by chance, but it shows that it's certainly possible to transmit information about the environment down the generations," says Lehner. "We don't know exactly why this happens, but it might be a form of biological forward-planning," adds the first author of the study and CRG Alumnus, Adam Klosin. "Worms are very short-lived, so perhaps they are transmitting memories of past conditions to help their descendants predict what their environment might be like in the future," adds Vavouri. Comparing the transgenes that were less active with those that had become activated by the higher temperature, Lehner and his team discovered crucial differences in a type of molecular 'tag' attached to the proteins packaging up the genes, known as histone methylation. Transgenes in animals that had only ever been kept at 20 degrees had high levels of histone methylation, which is associated with silenced genes, while those that had been moved to 25 degrees had largely lost the methylation tags. Importantly, they still maintained this reduced histone methylation when moved back to the cooler temperature, suggesting that it is playing an important role in locking the memory into the transgenes. The researchers also found that repetitive parts of the normal worm genome that look similar to transgene arrays also behave in the same way, suggesting that this is a widespread memory mechanism and not just restricted to artificially engineered genes. Explore further: Study shows how epigenetic memory is passed across generations More information: Klosin et al. Transgenerational transmission of environmental information in C. elegans. Science. April 21 2017. science.sciencemag.org/cgi/doi/10.1126/science.aah6412


Cebola I.,Imperial College London | Pasquali L.,Germans Trias i Pujol University Hospital and Research Institute | Pasquali L.,Josep Carreras Leukaemia Research Institute | Pasquali L.,CIBER ISCIII
Journal of Molecular Endocrinology | Year: 2015

Most of the genetic variation associated with diabetes, through genome-wide association studies, does not reside in protein-coding regions, making the identification of functional variants and their eventual translation to the clinic challenging. In recent years, highthroughput sequencing-based methods have enabled genome-scale high-resolution epigenomic profiling in a variety of human tissues, allowing the exploration of the human genome outside of the well-studied coding regions. These experiments unmasked tens of thousands of regulatory elements across several cell types, including diabetes-relevant tissues, providing new insights into their mechanisms of gene regulation. Regulatory landscapes are highly dynamic and cell-type specific and, being sensitive to DNA sequence variation, can vary with individual genomes. The scientific community is now in place to exploit the regulatory maps of tissues central to diabetes etiology, such as pancreatic progenitors and adult islets. This giant leap forward in the understanding of pancreatic gene regulation is revolutionizing our capacity to discriminate between functional and nonfunctional non-coding variants, opening opportunities to uncover regulatory links between sequence variation and diabetes susceptibility. In this review, we focus on the non-coding regulatory landscape of the pancreatic endocrine cells and provide an overview of the recent developments in this field. © 2016 Society for Endocrinology.


Navarro A.,University of Barcelona | Munoz C.,University of Barcelona | Diaz-Beya M.,Josep Carreras Leukaemia Research Institute | Gel B.,Institute of Predictive and Personalized Medicine of Cancer IMPPC | And 3 more authors.
PLoS ONE | Year: 2013

Background:In recent years, microRNA (miRNA) pathways have emerged as a crucial system for the regulation of tumorogenesis. miR-SNPs are a novel class of single nucleotide polymorphisms that can affect miRNA pathways.Design and Methods:We analyzed eight miR-SNPs by allelic discrimination in 141 patients with Hodgkin lymphoma and correlated the results with treatment-related toxicity, response, disease-free survival (DFS) and overall survival (OS).Results:The KRT81 (rs3660) GG genotype was associated with an increased risk of neurological toxicity (P = 0.016), while patients with XPO5 (rs11077) AA or CC genotypes had a higher rate of bleomycin-associated pulmonary toxicity (P = 0.048). Both miR-SNPs emerged as independent factors in the multivariate analysis. The XPO5 AA and CC genotypes were also associated with a lower response rate (P = 0.036). XPO5 (P = 0.039) and TRBP (rs784567) (P = 0.022) genotypes emerged as prognostic markers for DFS, and XPO5 was also associated with OS (P = 0.033). In the multivariate analysis, only XPO5 emerged as an independent prognostic factor for DFS (HR: 2.622; 95%CI 1.039-6.620; P = 0.041). Given the influence of XPO5 and TRBP as individual markers, we then investigated the combined effect of these miR-SNPs. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the shortest DFS (P = 0.008) and OS (P = 0.008).Conclusion:miR-SNPs can add useful prognostic information on treatment-related toxicity and clinical outcome in Hodgkin lymphoma and can be used to identify patients likely to be chemoresistant or to relapse. © 2013 Navarro et al.


Carreras E.,Josep Carreras Foundation | Carreras E.,Josep Carreras Leukaemia Research Institute
British Journal of Haematology | Year: 2015

Summary: Sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease of the liver, is one of the most relevant complications of endothelial origin that appears early after haematopoietic cell transplantation (HCT). Despite its relatively low incidence and the fact that most cases of SOS resolve spontaneously, the cases that evolve to multi-organ failure (MOF; severe SOS) have a mortality rate higher than 80% and represent one of the major clinical problems after HCT. For this reason, transplantation teams must have a pre-established policy regarding preventive measures in high-risk patients, strict daily control of weight and fluid balance during HCT, homogeneous diagnostic criteria, appropriate complementary studies for a correct differential diagnosis and measures to prevent and manage hepatorenal syndrome; in addition they must also be ready to start early treatment with defibrotide in patients with a possible severe SOS. Due to the lack of definitive evidence to enable the establishment of general recommendations in the management of SOS, this review analyses all of these aspects based on the author's personal experience. © 2014 John Wiley & Sons Ltd.

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