Centre For Genomic Regulation Research Articles

Cell scientist to watch – Elvan Böke

ABSTRACT Elvan Böke studied molecular biology and genetics at the Middle East Technical University in Ankara, Turkey. She then moved to the Cancer Research UK Manchester Institute (CRUK-MI) for a PhD with Iain Hagan, where she discovered that a PP1–PP2A phosphatase relay promotes mitotic exit in fission yeast. For her postdoc, she moved to the lab of Tim Mitchison at Harvard Medical School, Boston, USA, where she unraveled how the enigmatic Balbiani body is formed by an amyloid-like assembly mechanism in oocytes. Elvan established her group at the Centre for Genomic Regulation (CRG) Barcelona, Spain, in 2017, where her lab investigates oocyte biology and cellular dormancy. She was awarded an ERC Starting Grant in 2017 and an ERC Consolidator Grant in 2022. In 2021, Elvan became a member of the EMBO Young Investigator Network.

TIGER: The gene expression regulatory variation landscape of human pancreatic islets.

SUMMARYGenome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D.

Cell scientist to watch – Verena Ruprecht

ABSTRACT Verena Ruprecht received her PhD in Biophysics from the Johannes Kepler University in 2010 for her work on developing single-molecule super-resolution imaging tools in the lab of Gerhard Schütz. Following a research visit in Didier Marguet's lab at the Centre d'Immunologie de Marseille-Luminy (CIML) in France, she moved to the Institute of Science and Technology (IST) in Austria for a postdoc, working jointly with Carl-Philipp Heisenberg and Michael Sixt. There, she discovered a unique amoeboid cell migration mode in early zebrafish embryos, termed stable-bleb migration. Verena started her independent laboratory at the Centre for Genomic Regulation (CRG) in Barcelona, Spain, in September 2016. Her group combines genetic and biophysical methods with multi-scale imaging and mathematical modelling to study cellular dynamics in embryo development. In 2020, Verena was selected as an EMBO Young Investigator and in the same year awarded an HFSP Young Investigator Grant for a collaborative project to study the biophysics of zebrafish fertilization.

From research to rapid response: mass COVID-19 testing by volunteers at the Centre for Genomic Regulation

The COVID-19 pandemic has posed and is continuously posing enormous societal and health challenges worldwide. The research community has mobilized to develop novel projects to find a cure or a vaccine, as well as to contribute to mass testing, which has been a critical measure to contain the infection in several countries. Through this article, we share our experiences and learnings as a group of volunteers at the Centre for Genomic Regulation (CRG) in Barcelona, Spain. As members of the ORFEU project, an initiative by the Government of Catalonia to achieve mass testing of people at risk and contain the epidemic in Spain, we share our motivations, challenges and the key lessons learnt, which we feel will help better prepare the global society to address similar situations in the future.

From research to rapid response: mass COVID-19 testing by volunteers at the Centre for Genomic Regulation.

The COVID-19 pandemic has posed and is continuously posing enormous societal and health challenges worldwide. The research community has mobilized to develop novel projects to find a cure or a vaccine, as well as to contribute to mass testing, which has been a critical measure to contain the infection in several countries. Through this article, we share our experiences and learnings as a group of volunteers at the Centre for Genomic Regulation (CRG) in Barcelona, Spain. As members of the ORFEU project, an initiative by the Government of Catalonia to achieve mass testing of people at risk and contain the epidemic in Spain, we share our motivations, challenges and the key lessons learnt, which we feel will help better prepare the global society to address similar situations in the future.

Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency

BackgroundAlpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the ‘Z’ and ‘S’ variants – single-nucleotide variations (SNVs) that result in amino acid substitutions of E342K and E264V. However, SERPINA1 is highly polymorphic, with numerous potentially clinically relevant variants reported. Novel variants continue to be discovered, and without reports of pathogenicity, it can be difficult for clinicians to determine the best course of treatment.MethodsWe assessed the utility of next-generation sequencing (NGS) and predictive computational analysis to guide the diagnosis of patients suspected of having AATD. Blood samples on serum separator cards were submitted to the DNA1 Advanced Screening Program (Biocerna LLC, Fulton, Maryland, USA) by physicians whose patients were suspected of having AATD. Laboratory analyses included quantification of serum AAT levels, qualitative analysis by isoelectric focusing, and targeted genotyping and NGS of the SERPINA1 gene. Molecular modeling software UCSF Chimera (University College of San Francisco, CA) was used to visualize the positions of amino acid changes as a result of rare/novel SNVs. Predictive software was used to assess the potential pathogenicity of these variants; methods included a support vector machine (SVM) program, PolyPhen-2 (Harvard University, Cambridge, MA), and FoldX (Centre for Genomic Regulation, Barcelona, Spain).ResultsSamples from 23 patients were analyzed; 21 rare/novel sequence variants were identified by NGS, including splice variants (n = 2), base pair deletions (n = 1), stop codon insertions (n = 2), and SNVs (n = 16). Computational modeling of protein structures caused by the novel SNVs showed that 8 were probably deleterious, and two were possibly deleterious. For the majority of probably/possibly deleterious SNVs (I50N, P289S, M385T, M221T, D341V, V210E, P369H, V333M and A142D), the mechanism is probably via disruption of the packed hydrophobic core of AAT. Several deleterious variants occurred in combination with more common deficiency alleles, resulting in very low AAT levels.ConclusionsNGS and computational modeling are useful tools that can facilitate earlier, more precise diagnosis, and consideration for AAT therapy in AATD.

Cellular circadian period length inversely correlates with HbA1c levels in individuals with type 2 diabetes.

The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes. We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters. We observed a significant inverse correlation (ρ = -0.592; p < 0.05) between HbA1c values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression. We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans. RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.

An interview with James Sharpe.

James Sharpe is a developmental biologist who studies the process of limb development using a multi-disciplinary approach, combining experimental systems, imaging and computer modelling. Formerly based at the Centre for Genomic Regulation in Barcelona, James was recently appointed Head of EMBL Barcelona. We caught up with James at the British Society for Developmental Biology Spring Meeting to ask him about his research, his thoughts on computational modelling, and his vision for the new EMBL Barcelona site.

Centre for Genomic Regulation - a hub for Integrative Biology in Barcelona.

Centre for Genomic Regulation - a hub for Integrative Biology in Barcelona.

Quantitative Analysis of Candida Cell Wall Components by Flow Cytometry with Triple-Fluorescence Staining

This work was supported by the European Commission within the FP7 Framework Programme [Fungitect-Grant No 602125]. We also thank Thomas Sauer, Vienna Biocenter Campus (VBC), Austria, for technical support at the FACS facility of the MFPL, Karl Kuchler, MFPL-Department of Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria and Ernst Thuer, Centre for Genomic Regulation, Barcelona, Spain, for advice on statistical approaches. Neil Gow acknowledges the support of the Wellcome Trust and the MRC Centre for Medical Mycology

Chromatin and Epigenetics at the Forefront: Finding Clues among Peaks.

The Keystone Symposium on Chromatin and Epigenetics, organized by Luciano Di Croce (Center for Genomic Regulation, Spain) and Yang Shi (Harvard Medical School, USA), took place 20 to 24 March 2016 at Whistler (British Columbia, Canada). The symposium brought together some of the most outstanding scientists studying how chromatin structure and epigenetic mechanisms regulate gene function in both development and disease. Junior scientists had the opportunity to interact with experienced researchers by presenting their work and discussing ideas and novel hypotheses. In order to foster interaction and networking, the scientific agenda was balanced with an extended social agenda. This meeting review describes several of the most provocative and exciting talks from the symposium, revealing how fast this research field is evolving and the profound impact it will have on human health.

Cell scientist to watch – Meritxell Huch

ABSTRACT After completing her BSc in pharmacology at University of Barcelona, Spain, Meritxell Huch pursued her PhD in the laboratory of Cristina Fillat at the Centre for Genomic Regulation (CRG) in Barcelona. Wanting to move into more basic research, Meri trained as a postdoc with Hans Clevers at the Hubrecht Institute in the Netherlands. In her postdoctoral research, she successfully established a liver organoid culture that earned her the National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs) prize in 2013. Meri joined the Gurdon Institute in February 2014 and is currently a Wellcome Trust Sir Henry Dale Research Fellow. She is interested in the mechanisms responsible for adult tissue regeneration in the liver and the pancreas, particularly in identifying stem cell populations that respond to damage and the intracellular mechanisms regulating their activation.

Ordered Recruitment of Transcription and Chromatin Remodeling Factors to a Cell Cycle– and Developmentally Regulated Promoter

(Cell 97, 299–311; April 30, 1999) Concerns about duplicated images in Cosma et al. (Cell, 1999) and Cosma et al. (2001, Mol. Cell 7, 1213–1220) were brought to our attention by a reader. We, the editors of Cell and Molecular Cell, have investigated the matter, communicating with the corresponding author, Dr. Kim Nasmyth; the first author, Dr. Pia Cosma; The Research Institute of Molecular Pathology (IMP), where the research in question was conducted; and the Center for Genomic Regulation, Dr. Cosma’s current institute, which conducted its own investigation. The IMP located Dr. Cosma’s notebooks and provided her with high-resolution copies. As part of our investigation, Dr. Cosma brought those copies to the Cell Press office, where we went through them with her, identifying data for the figures in the paper. The notebooks contained original images, alternate exposures, and/or replicate data for most of the figures in the papers, providing support for the reported findings. In a few instances, original data could not be located, making it difficult to assess the concerns raised about those specific data panels. While we understand the reasons that the figures in the paper were flagged by the community, in our judgment the burden of proof for determining inappropriate data handling or image duplication has not been met. Furthermore, the available original data support the findings of the papers. With these things in mind, based on the information available to us at this time, we have decided not to take any further action. This statement is to notify the community of our investigation and findings. Ordered Recruitment of Transcription and Chromatin Remodeling Factors to a Cell Cycle– and Developmentally Regulated PromoterCosma et al.CellApril 30, 1999In BriefGene activation in eukaryotes requires chromatin remodeling complexes like Swi/Snf and histone acetylases like SAGA. How these factors are recruited to promoters is not yet understood. Using CHIP, we measured recruitment of Swi/Snf, SAGA, the repressor Ash1p, and transcription factors Swi5p and SBF to the HO endonuclease promoter as cells progress through the yeast cell cycle. Swi5p’s entry into nuclei at the end of anaphase recruits Swi/Snf, which then recruits SAGA. These two factors then facilitate SBF’s binding. Full-Text PDF Open Archive

Mitochondrial Ancestor Joined Late with Other Bacteria, then Shed Genes

The host cell that engulfed the alpha-proteobacterial ancestor of mitochondria billions of years ago was complex and full of pathways and processes from diverse other bacteria, according to Alexandros Pittis and Toni Gabaldon from the Centre for Genomic Regulation in Barcelona, Spain. It apparently partnered late, as “mito-late,” during eukaryogenesis, and subsequently shed many genes en route to modern times. Details about mito-late appeared 3 March 2016 in Nature (doi:10.1038/nature16941), while details about mitochondrial gene shedding appeared 24 February 2016 in Cell Systems (doi.org/10.1016/j.cels.2016.01.013).

Special issue: epigenetics: introduction.

Epigenetic studies focus on changes in genetic information that rely on histone modification, which complements information encoded by the DNA sequence. Research in this rapidly expanding field has greatly contributed to a better understanding of processes such as gene regulation, chromatin structure, and cell differentiation and disease. The most recent advances in this area are reviewed in the collection of papers included in this Special Issue.

Mathematical model to study the nonlinear influence of Dyrk1A in actin polymerization

Event Abstract Back to Event Mathematical model to study the nonlinear influence of Dyrk1A in actin polymerization German A. Patterson1* and Mara Dierssen1 1 Center for Genomic Regulation, Spain Dyrk1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. It is believed that Dyrk1A plays a significant role in signaling pathways regulating cell proliferation and may be involved in neuron development. On the one hand, it has been reported that overexpression of Dyrk1A is sufficient to produce the dendritic alterations, in particular, it was shown that changes in Dyrk1A gene dosage strongly alter the dendritic arborization processes characterized by a reduction of neurite outgrowth [Martinez de Legran et al., 2012]. On the other hand, it was found that cells in Dyrk1A+/- mouse, a model lacking one copy of Dyrk1A, were less branched and less spinous than WT. This results suggest that Dyrk1A is affecting cellular pathways involved in neural development in a way that dosage changes lead to similar alteration regardless the direction of this change [Benavides-Piccione et al., 2005]. Here, we present a simple mathematical model that may explain both alterations observed in Dyrk1A+/- and Ts65Dn. It is based on a model proposed by Park et al., which describes a regulatory mechanism for Neural Wiskott–Aldrich syndrome protein (N-WASP) activity through Dyrk1A phosphorylation and how it regulates the actin filament assembly [Park et al., 2011]. In this work, we present a full characterization of the behavior of the system as a function of different set of parameters. We study how Dyrk1A may affect the dynamics of the system and how Dyrk1A dosage may regulate the actin polymerization. We believe that these findings may shed same light on how Dyrk1A affects cellular processes such as morphogenesis and neuronal differentiation. References R. Benavides-Piccione, M. Dierssen, I. Ballesteros-Yáñez, M. Martínez de Lagrán, M.L. Arbonés, V. Fotaki, J. DeFelipe, G.N. Elston, Alterations in the phenotype of neocortical pyramidal cells in the Dyrk1A+/− mouse, Neurobiology of Disease, Volume 20, Issue 1, October 2005, Pages 115-122, ISSN 0969-9961, doi:10.1016/j.nbd.2005.02.004. M. Martinez de Lagran, R. Benavides-Piccione, I. Ballesteros-Yañez, M. Calvo, M. Morales, C. Fillat, J. DeFelipe, G. J. A. Ramakers, and M. Dierssen, Dyrk1A Influences Neuronal Morphogenesis Through Regulation of Cytoskeletal Dynamics in Mammalian Cortical Neurons, Cereb. Cortex (2012) 22 (12): 2867-2877, doi:10.1093/cercor/bhr362 Joongkyu Park, Jee Young Sung, Joohyun Park, Woo-Joo Song, Sunghoe Chang, and Kwang Chul Chung, Dyrk1A negatively regulates the actin cytoskeleton through threonine phosphorylation of N-WASP, J Cell Sci 2012 125:67-80, doi:10.1242/jcs.086124 Keywords: Cellular Pathway Analysis and Simulation, Morphogenesis, actin polymerization, DYRK1A, NWASP Conference: B·DEBATE | A Dialogue with the Cerebral Cortex: Cortical Function and Interfacing (Workshop), Barcelona, Spain, 29 Apr - 30 Apr, 2015. Presentation Type: Poster Presentation Topic: SESSION 1: Cortical Function and Computations Citation: Patterson GA and Dierssen M (2015). Mathematical model to study the nonlinear influence of Dyrk1A in actin polymerization. Front. Syst. Neurosci. Conference Abstract: B·DEBATE | A Dialogue with the Cerebral Cortex: Cortical Function and Interfacing (Workshop). doi: 10.3389/conf.fnsys.2015.06.00006 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Apr 2015; Published Online: 06 May 2015. * Correspondence: Dr. German A Patterson, Center for Genomic Regulation, Barcelona, Spain, german.patterson@crg.eu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers German A Patterson Mara Dierssen Google German A Patterson Mara Dierssen Google Scholar German A Patterson Mara Dierssen PubMed German A Patterson Mara Dierssen Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

MEK1 inactivates Myt1 to regulate Golgi membrane fragmentation and mitotic entry in mammalian cells

The pericentriolar stacks of Golgi cisternae are separated from each other in G2 and fragmented extensively during mitosis. MEK1 is required for Golgi fragmentation in G2 and for the entry of cells into mitosis. We now report that Myt1 mediates MEK1's effects on the Golgi complex. Knockdown of Myt1 by siRNA increased the efficiency of Golgi complex fragmentation by mitotic cytosol in permeabilized and intact HeLa cells. Myt1 knockdown eliminated the requirement of MEK1 in Golgi fragmentation and alleviated the delay in mitotic entry due to MEK1 inhibition. The phosphorylation of Myt1 by MEK1 requires another kinase but is independent of RSK, Plk, and CDK1. Altogether our findings reveal that Myt1 is inactivated by MEK1 mediated phosphorylation to fragment the Golgi complex in G2 and for the entry of cells into mitosis. It is known that Myt1 inactivation is required for CDK1 activation. Myt1 therefore is an important link by which MEK1 dependent fragmentation of the Golgi complex in G2 is connected to the CDK1 mediated breakdown of Golgi into tubules and vesicles in mitosis.

Global Challenges in Stem Cell Research and the Many Roads Ahead

The field of stem cell research has grown to include a vibrant international community of scientists and clinicians who come from both academia and industry and who strive to shed light on the biology of these remarkable cells and find applications in drug discovery, disease modeling, and regenerative medicine.

Correction: Genes Confer Similar Robustness to Environmental, Stochastic, and Genetic Perturbations in Yeast

The affiliations listed for the author are incorrect. The correct affiliations should read: 1 European Molecular Biology Laboratory (EMBL) - Centre for Genomic Regulation (CRG) Systems Biology Unit, Barcelona, Spain, 2 Institucio Catalana de Recerca i Estudis Avancats (ICREA), Centre for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Spain.

BioEssays 10/2009

Cover Photograph: A superposition of a fish with colour patterning produced by a gene expression network involving a “paradoxical” relationship between two genes, of the type A inhibits B; B activates A, upon a computer simulation of the same. When explored in terms of spatial resolution, apparent paradoxes represented by simple connectivity diagrams produce undulating patterns; in other situations they produce temporal oscillations. To read more on this topic, see the article by Mark Isalan on pages 1110–1115. Fish image reproduced with kind permission from Anka Zolnierzak; computer simulation image reproduced with kind permission from Luciano Marcon, Centre for Genomic Regulation, Barcelona, Spain.