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Modeling dynamics and function of bone marrow cells in mouse liver regeneration

  • Pedone, Elisa, 1985-
  • Olteanu, Vlad Aris
  • Marucci, Lucia
  • Muñoz-Martin, Maria Isabel
  • Youssef, Sameh A.
  • de Bruin, Alain
  • Cosma, Maria Pia, 1970-
In rodents and humans, the liver can efficiently restore its mass after hepatectomy. This is largely attributed to the proliferation and cell cycle re-entry of hepatocytes. On the other hand, bone marrow cells (BMCs) migrate into the liver after resection. Here, we find that a block of BMC recruitment into the liver severely impairs its regeneration after the surgery. Mobilized hematopoietic stem and progenitor cells (HSPCs) in the resected liver can fuse with hepatocytes, and the hybrids proliferate earlier than the hepatocytes. Genetic ablation of the hybrids severely impairs hepatocyte proliferation and liver mass regeneration. Mathematical modeling reveals a key role of bone marrow (BM)-derived hybrids to drive proliferation in the regeneration process, and predicts regeneration efficiency in experimentally non-testable conditions. In conclusion, BM-derived hybrids are essential to trigger efficient liver regeneration after hepatectomy., This work was supported by an ERC grant (242630-RERE to M.P.C.), the Ministerio de Economia y Competitividad and FEDER funds (SAF2011-28580, BFU2014-54717-P, and BFU2015-71984-ERC to M.P.C.), an AGAUR grant from Secretaria d'Universitats i Investigació del Departament d'Economia i Coneixement de la Generalitat de Catalunya (2014SGR1137 to M.P.C.), an MRC grant (MR/N021444/1 to L.M.), BrisSynBio, BBSRC/EPSRC Synthetic Biology Research Centre (BB/L01386X/1 to L.M.), and Engineering and Physical Sciences Research Council (EP/I013717/1 to V.A.O.). We acknowledge support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017 and of the CERCA Programme/Generalitat de Catalunya.

Major roles for pyrimidine dimers, nucleotide excision repair, and ATR in the alternative splicing response to UV irradiation

  • Muñoz, Manuel Javier
  • Nieto Moreno, Nicolás
  • Giono, Luciana E.
  • Cambindo Botto, Adrián E.
  • Dujardin, Gwendal
  • Bastianello, Giulia
  • Lavore, Stefania
  • Torres Méndez, Antonio
  • Menck, Carlos Frederico Martins
  • Blencowe, Benjamin J.
  • Irimia, Manuel
  • Foiani, Marco
  • Kornblihtt, Alberto R.
We have previously found that UV irradiation promotes RNA polymerase II (RNAPII) hyperphosphorylation and subsequent changes in alternative splicing (AS). We show now that UV-induced DNA damage is not only necessary but sufficient to trigger the AS response and that photolyase-mediated removal of the most abundant class of pyrimidine dimers (PDs) abrogates the global response to UV. We demonstrate that, in keratinocytes, RNAPII is the target, but not a sensor, of the signaling cascade initiated by PDs. The UV effect is enhanced by inhibition of gap-filling DNA synthesis, the last step in the nucleotide excision repair pathway (NER), and reduced by the absence of XPE, the main NER sensor of PDs. The mechanism involves activation of the protein kinase ATR that mediates the UV-induced RNAPII hyperphosphorylation. Our results define the sequence UV-PDs-NER-ATR-RNAPII-AS as a pathway linking DNA damage repair to the control of both RNAPII phosphorylation and AS regulation., A.R.K. and M.J.M. received support from the Agencia Nacional de Promoción Científica y Tecnológica of Argentina (PICT-2011 1617, PICT-2014 2582), the Universidad de Buenos Aires (UBACYT 20020130100152BA), and the Alberto J. Roemmers Foundation. G.D. was supported by Marie Curie International Outgoing Fellowship within the EU Seventh Framework Programme for Research and Technological Development (FP7/2007-2013) under grant agreement 275632. B.J.B. is supported by grants from the Canadian Institutes of Health Research (FDN 148434). M.I. is supported by grants from the European Research Council (ERC-StG-LS2- 637591) and from Ministerio de Economía y Competitividad (BFU2014-55076-P; MINECO). A.T.-M. is supported by an FPI-SO fellowship from the Spanish Ministry of Economy and Competitiveness. M.F. is supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and Telethon-Italy. G.B. is recipient of a fellowship from the University of Milan. S.L. is an employee of IFOM Cell Biology Unit. M.J.M., L.E.G., and A.R.K. are career investigators and N.N.M. and A.E.C.B. are recipients of a graduate student fellowship from the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina (CONICET). A.R.K. is a Senior International Research Scholar of the Howard Hughes Medical Institute.

Wolf-Hirschhorn syndrome candidate 1 is necessary for correct hematopoietic and B cell development

  • Campos Sańchez, Elena
  • Deleyto Seldas, Nerea
  • Domínguez, Verónica
  • Carrillo, Enrique
  • Ura, Kiyoe
  • Rocha, Pedro P.
  • Kim, Jung Hyun
  • Aljoufi, Arafat
  • Esteve-Codina, Anna
  • Dabad, Marc
  • Gut, Marta
  • Heyn, Holger
  • Kaneda, Yasufumi
  • Nimura, Keisuke
  • Skok, Jane Amanda
  • Martínez Frías, María Luísa
  • Cobaleda, César
Immunodeficiency is one of the most important causes of mortality associated with Wolf-Hirschhorn syndrome (WHS), a severe rare disease originated by a deletion in chromosome 4p. The WHS candidate 1 (WHSC1) gene has been proposed as one of the main genes responsible for many of the alterations in WHS, but its mechanism of action is still unknown. Here, we present in vivo genetic evidence showing that Whsc1 plays an important role at several points of hematopoietic development. Particularly, our results demonstrate that both differentiation and function of Whsc1-deficient B cells are impaired at several key developmental stages due to profound molecular defects affecting B cell lineage specification, commitment, fitness, and proliferation, demonstrating a causal role for WHSC1 in the immunodeficiency of WHS patients., Research at C.C.'s lab was partially supported by FEDER (Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III) (PI13/00160 and PI14/00025), Fundación Inocente Inocente, and the ARIMMORA EU/FP7 project and by donations from the Asociación Española del Síndrome de Wolf Hirschhorn (AESWH), the Fundación Síndrome de Wolf-Hirschhorn or 4p- (FSWH4p), FECYT Precipita, and Fundación Ramón Areces. E.C.-S. was partially supported by a JAE-PreDoc fellowship from the Spanish National Research Council (CSIC, FEDER) and was a Residencia de Estudiantes Fellow. N.D.-S. was partially supported by a JAE-intro studentship from the Spanish National Research Council (CSIC) (JAEINT_15_01981). Research at K.U.'s lab was partially supported by the JSTP PRESTO program (4201) and Grants-in-Aid for Scientific Research (22131003 and 15H01345) from MEXT of Japan. P.P.R. is a National Cancer Center and American Society of Hematology Fellow. J.A.S. is a Leukemia & Lymphoma Society (LLS) scholar and NCC and ASH fellow and is supported by NIH grants R01GM086852 and R01GM112192. Research at M.L.M.F.'s lab was partially supported by Instituto de Salud Carlos III and Fundación 1.000 sobre Defectos Congénitos. CIBERER is an initiative of ISCIII, Ministry of Economy and Competitiveness of Spain. V.D. was partially supported by Ministry of Science and Innovation through the Programa tecnicos de apoyo (PTA) from 2012 to 2014. A.E.-C. is funded by the RED-BIO project of the Spanish National Bioinformatics Institute (INB) under grant number PT13/0001/0044. The INB is funded by the Spanish National Health Institute Carlos III (ISCIII) and the Spanish Ministry of Economy and Competitiveness (MINECO). M.D. was funded by the Ministry of Economy and Competitiveness of Spain (PTA2014-09515-I). H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). P.P.R. was financed by NIH grant K99GM117302.

Evaluating the genetics of common variable immunodeficiency: monogenetic model and beyond

  • Valles Ibáñez, Guillem de, 1986-
  • Hernández Rodríguez, Jessica
  • Laayouni, Hafid, 1968-
  • Cuscó Martí, Ivon, 1973-
  • Codina i Solà, Marta, 1988-
  • Batlle Masó, Laura
  • Solís Moruno, Manuel
  • Marquès i Bonet, Tomàs, 1975-
  • Bosch Fusté, Elena
  • Casals López, Ferran
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15-24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls., This study was funded by grants SAF2012-35025 and SAF2015-68472-C2-2-R from the Ministerio de Economía y Competitividad (Spain) and FEDER (EU) to FC; by Direcció General de Recerca, Generalitat de Catalunya (2014SGR-866 and 2017SGR-702) to FC and EB; to EB by grant BFU2016-77961-P from Ministerio de Economía, Industria y Competitividad (Spain) AEI (Spain) and FEDER (EU); by Instituto de Salud Carlos III, grant PI14/00405, cofinanced by the European Regional Development Fund (ERDF) to RC; partially funded by CERCA Programme/Generalitat de Catalunya (JIA), and SAF2015-68472-C2-1-R grant from the Spanish Ministry of Economy and Competitiveness co-financed by European Regional Development Fund (ERDF) to JIA; GV-I was supported by grant BES-2012-051794; JH-R was supported by grant BES-2013-064333. TMB is supported by U01 MH106874 grant, Howard Hughes International Early Career, Obra Social “La Caixa” and Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya. All phases of this study were supported by the projects PI12/01990 and PI15/01094 to LA and PI13/00676 to MJ. This work was also supported by the Jeffrey Modell Foundation. This study makes use of data generated by the Medical Genome Project. A full list of the investigators who contributed to the generation of the data is available from http://www.medicalgenomeproject.com/en. Funding for the project was provided by the Spanish Ministry of Economy and Competitiveness, projects I + D + i 2008, Subprograma de actuaciones Científicas y Tecnológicas en Parques Científicos y Tecnológicos (ACTEPARQ 2009) and ERFD.

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

  • Dall'Olio, Giovanni Marco, 1983-
  • Laayouni, Hafid, 1968-
  • Luisi, Pierre, 1985-
  • Sikora, Martin, 1976-
  • Montanucci, Ludovica, 1978-
  • Bertranpetit, Jaume, 1952-
Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway., This work was funded by grant BFU2010-19443 (subprogram BMC) awarded to JB by Ministerio de Ciencia y Tecnología (Spain), and the Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101). GMD is supported by a FPI fellowship (BES-2009-017731) from the Ministerio de Ciencia y Tecnología, (Spain). PL is supported by a PhD fellowship from “Acción Estratégica de Salud, 2008-2011” from Instituto de Salud Carlos III and LM is supported by a postdoctoral fellowship from the Juan de la Cierva Program of the Spanish Ministry of Science and Innovation (MICINN).

Spatiotemporal proteomic profiling of Huntington's disease inclusions reveals widespread loss of protein function

  • Hosp, Fabian
  • Gutiérrez Ángel, Sara
  • Schaefer, Martin H.
  • Cox, Jürgen
  • Meissner, Felix
  • Hipp, Mark Steffen
  • Hartl, F. Ulrich
  • Klein, Rüdiger
  • Dudanova, Irina
  • Mann, Matthias
Aggregation of polyglutamine-expanded huntingtin exon 1 (HttEx1) in Huntington's disease (HD) proceeds from soluble oligomers to late-stage inclusions. The nature of the aggregates and how they lead to neuronal dysfunction is not well understood. We employed mass spectrometry (MS)-based quantitative proteomics to dissect spatiotemporal mechanisms of neurodegeneration using the R6/2 mouse model of HD. Extensive remodeling of the soluble brain proteome correlated with insoluble aggregate formation during disease progression. In-depth and quantitative characterization of the aggregates uncovered an unprecedented complexity of several hundred proteins. Sequestration to aggregates depended on protein expression levels and sequence features such as low-complexity regions or coiled-coil domains. In a cell-based HD model, overexpression of a subset of the sequestered proteins in most cases rescued viability and reduced aggregate size. Our spatiotemporally resolved proteome resource of HD progression indicates that widespread loss of cellular protein function contributes to aggregate-mediated toxicity., The research leading to these results has received funding from the Munich Cluster for Systems Neurology “SyNergy,” the European Research Council Synergy grant “ToPAG—Toxic protein aggregation in neurodegeneration” (ERC-2012-SyG_318987-ToPAG), and the Max Planck Society for the Advancement of Science.

Constitutively active SMAD2/3 are broad-scope potentiators of transcription-factor-mediated cellular reprogramming

  • Ruetz, Tyson Joel
  • Pfisterer, Ulrich
  • Di Stefano, Bruno, 1984-
  • Ashmore, James
  • Beniazza, Meryam
  • Tian, Tian V.
  • Kaemena, Daniel F.
  • Tosti, Luca
  • Tan, Wenfang
  • Manning, Jonathan R.
  • Chantzoura, Eleni
  • Ottosson, Daniella Rylander
  • Collombet, Samuel
  • Johnsson, Anna E.
  • Cohen, Erez
  • Yusa, Kosuke
  • Linnarsson, Sten
  • Graf, T. (Thomas)
  • Parmar, Malin
  • Kaji, Keisuke
Reprogramming of cellular identity using exogenous expression of transcription factors (TFs) is a powerful and exciting tool for tissue engineering, disease modeling, and regenerative medicine. However, generation of desired cell types using this approach is often plagued by inefficiency, slow conversion, and an inability to produce mature functional cells. Here, we show that expression of constitutively active SMAD2/3 significantly improves the efficiency of induced pluripotent stem cell (iPSC) generation by the Yamanaka factors. Mechanistically, SMAD3 interacts with reprogramming factors and co-activators and co-occupies OCT4 target loci during reprogramming. Unexpectedly, active SMAD2/3 also markedly enhances three other TF-mediated direct reprogramming conversions, from B cells to macrophages, myoblasts to adipocytes, and human fibroblasts to neurons, highlighting broad and general roles for SMAD2/3 as cell-reprogramming potentiators. Our results suggest that co-expression of active SMAD2/3 could enhance multiple types of TF-based cell identity conversion and therefore be a powerful tool for cellular engineering., This work was supported by the ERC (grants ROADTOIPS 261075 to K.K. and BRAINCELL 261063 to S.L. and iN-Brain 309712 to M.P.), the BBSRC (project grant BB/L023474/1 to K.K.), the Anne Rowling Regenerative Neurology Clinic (K.K.), the Swedish Research Council (grant STARGET to S.L. and grants 521-2012-5624 and 521-2013-3347 to M.P.), and the Wellcome Trust (grant WT098051 to K.Y.). T.R., L.T., J.A., and D.F.K. are funded by a Darwin Trust scholarship, a CMVM scholarship, and Principal's Career Development scholarship from the University of Edinburgh, respectively. D.F.K. is supported by the BBSRC (EASTBIO doctoral training partnership). T.V.T. is supported by a Juan de la Cierva postdoctoral fellowship (MINECO, FJCI-2014-22946). B.D.S. was supported by an EMBO long-term fellowship (ALTF 1143-2015). K.K. is an MRC senior non-clinical fellow (MR/N008715/1). M.P. is a New York Stem Cell Foundation Robertson Investigator.

Assessment of the Combined Effect of Epstein-Barr Virus and Plasmodium falciparumInfections on Endemic Burkitt Lymphoma Using a Multiplex Serological Approach

  • Aguilar, Ruth
  • Casabonne, Delphine
  • O’Callaghan-Gordo, Cristina
  • Vidal, Marta
  • Campo, Joseph J.
  • Mutalima, Nora
  • Angov, Evelina
  • Dutta, Sheetij
  • Gaur, Deepak
  • Chitnis, Chetan E.
  • Chauhan, Virander
  • Michel, Angelika
  • de Sanjosé, Silvia
  • Waterboer, Tim
  • Kogevinas, Manolis
  • Newton, Rob
  • Dobaño, Carlota
Epstein-Barr virus (EBV) is a necessary cause of endemic Burkitt lymphoma (eBL), while the role of Plasmodium falciparum in eBL remains uncertain. This study aimed to generate new hypotheses on the interplay between both infections in the development of eBL by investigating the IgG and IgM profiles against several EBV and P. falciparum antigens. Serum samples collected in a childhood study in Malawi (2005-2006) from 442 HIV-seronegative children (271 eBL cases and 171 controls) between 1.4 and 15 years old were tested by quantitative suspension array technology against a newly developed multiplex panel combining 4 EBV antigens [Z Epstein-Barr replication activator protein (ZEBRA), early antigen-diffuse component (EA-D), EBV nuclear antigen 1, and viral capsid antigen p18 subunit (VCA-p18)] and 15 P. falciparum antigens selected for their immunogenicity, role in malaria pathogenesis, and presence in different parasite stages. Principal component analyses, multivariate logistic models, and elastic-net regressions were used. As expected, elevated levels of EBV IgG (especially against the lytic antigens ZEBRA, EA-D, and VCA-p18) were strongly associated with eBL [high vs low tertile odds ratio (OR) = 8.67, 95% confidence interval (CI) = 4.81-15.64]. Higher IgG responses to the merozoite surface protein 3 were observed in children with eBL compared with controls (OR = 1.29, 95% CI = 1.02-1.64), showing an additive interaction with EBV IgGs (OR = 10.6, 95% CI = 5.1-22.2, P = 0.05). Using elastic-net regression models, eBL serological profile was further characterized by lower IgM levels against P. falciparum preerythrocytic-stage antigen CelTOS and EBV lytic antigen VCA-p18 compared with controls. In a secondary analysis, abdominal Burkitt lymphoma had lower IgM to EBV and higher IgG to EA-D levels than cases with head involvement. Overall, this exploratory study confirmed the strong role of EBV in eBL and identified differential IgG and IgM patterns to erythrocytic vs preerythrocytic P. falciparum antigens that suggest a more persistent/chronic malaria exposure and a weaker IgM immune response in children with eBL compared with controls. Future studies should continue exploring how the malaria infection status and the immune response to P. falciparum interact with EBV infection in the development of eBL.

Alternative transcriptional regulation in genome-reduced bacteria

  • Miravet Verde, Samuel
  • Lloréns Rico, Verónica, 1989-
  • Serrano Pubull, Luis, 1982-
Transcription is a core process of bacterial physiology, and as such it must be tightly controlled, so that bacterial cells maintain steady levels of each RNA molecule in homeostasis and modify them in response to perturbations. The major regulators of transcription in bacteria (and in eukaryotes) are transcription factors. However, in genome-reduced bacteria, the limited number of these proteins is insufficient to explain the variety of responses shown upon changes in their environment. Thus, alternative regulators may play a central role in orchestrating RNA levels in these microorganisms. These alternative mechanisms rely on intrinsic features within DNA and RNA molecules, suggesting they are ancestral mechanisms shared among bacteria that could have an increased relevance on transcriptional regulation in minimal cells. In this review, we summarize the alternative elements that can regulate transcript abundance in genome-reduced bacteria and how they contribute to the RNA homeostasis at different levels., We acknowledge support of the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program under agreement No 670216 (MYCOCHASSIS) and the Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa 2013-2017′.

Species-specific modulation of food-search behavior by respiration and chemosensation in Drosophila larvae

  • Kim, Daeyeon
  • Alvarez, Mar
  • Lechuga, Laura M
  • Louis, Matthieu
Animals explore their environment to encounter suitable food resources. Despite its vital importance, this behavior puts individuals at risk by consuming limited internal energy during locomotion. We have developed a novel assay to investigate how food-search behavior is organized in Drosophila melanogaster larvae dwelling in hydrogels mimicking their natural habitat. We define three main behavioral modes: resting at the gel's surface, digging while feeding near the surface, and apneic dives. In unstimulated conditions, larvae spend most of their time digging. By contrast, deep and long exploratory dives are promoted by olfactory stimulations. Hypoxia and chemical repellents impair diving. We report remarkable differences in the dig-and-dive behavior of D. melanogaster and the fruit-pest D. suzukii. The present paradigm offers an opportunity to study how sensory and physiological cues are integrated to balance the limitations of dwelling in imperfect environmental conditions and the risks associated with searching for potentially more favorable conditions., We acknowledge support of the Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa 2013-2017', as well as the support of the CERCA Programme/Generalitat de Catalunya. This work was supported by funding from the Spanish Ministry of Science and Innovation (MICINN, BFU2008-00362 and BFU2011-26208), the EMBL/CRG Systems Biology Program and the EU FET-Open grant MINIMAL.

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