Person:
Badia-Careaga, Claudio

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Claudio
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Badia-Careaga
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CNIC
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2015 - 201942020 - 20223
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Author: Manzanares, Miguel ×

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Now showing 1 - 7 of 7
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    Essential Roles of Cohesin STAG2 in Mouse Embryonic Development and Adult Tissue Homeostasis.
    (Cell Press, 2020-08-11) Lapi, Eleonora; Badia-Careaga, Claudio; Cossío, Itziar; Giménez-Llorente, Daniel; Rodríguez-Corsino, Miriam; Andrada, Elena; Hidalgo, Andres; Manzanares, Miguel; Real Arribas, Francisco; Losada, Ana; De Koninck, Magali; Unión Europea; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Fundación ProCNIC
    Cohesin mediates sister chromatid cohesion and 3D genome folding. Two versions of the complex carrying STAG1 or STAG2 coexist in somatic vertebrate cells. STAG2 is commonly mutated in cancer, and germline mutations have been identified in cohesinopathy patients. To better understand the underlying pathogenic mechanisms, we report the consequences of Stag2 ablation in mice. STAG2 is largely dispensable in adults, and its tissue-wide inactivation does not lead to tumors but reduces fitness and affects both hematopoiesis and intestinal homeostasis. STAG2 is also dispensable for murine embryonic fibroblasts in vitro. In contrast, Stag2-null embryos die by mid-gestation and show global developmental delay and defective heart morphogenesis, most prominently in structures derived from secondary heart field progenitors. Both decreased proliferation and altered transcription of tissue-specific genes contribute to these defects. Our results provide compelling evidence on cell- and tissue-specific roles of different cohesin complexes and how their dysfunction contributes to disease.
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    The pluripotency factor NANOG controls primitive hematopoiesis and directly regulates Tal1
    (EMBO Press, 2019-04-01) Sainz de Aja, Julio; Menchero, Sergio; Rollan, Isabel; Barral, Antonio; Tiana, Maria; Jawaid, Wajid; Cossio, Itziar; Alvarez, Alba; Carreño-Tarragona, Gonzalo; Badia-Careaga, Claudio; Nichols, Jennifer; Göttgens, Berthold; Isern, Joan; Manzanares, Miguel; Ministerio de Ciencia, Innovación y Universidades (España); Wellcome Trust; Fundación ProCNIC
    Progenitors of the first hematopoietic cells in the mouse arise in the early embryo from Brachyury-positive multipotent cells in the posterior-proximal region of the epiblast, but the mechanisms that specify primitive blood cells are still largely unknown. Pluripotency factors maintain uncommitted cells of the blastocyst and embryonic stem cells in the pluripotent state. However, little is known about the role played by these factors during later development, despite being expressed in the postimplantation epiblast. Using a dual transgene system for controlled expression at postimplantation stages, we found that Nanog blocks primitive hematopoiesis in the gastrulating embryo, resulting in a loss of red blood cells and downregulation of erythropoietic genes. Accordingly, Nanog-deficient embryonic stem cells are prone to erythropoietic differentiation. Moreover, Nanog expression in adults prevents the maturation of erythroid cells. By analysis of previous data for NANOG binding during stem cell differentiation and CRISPR/Cas9 genome editing, we found that Tal1 is a direct NANOG target. Our results show that Nanog regulates primitive hematopoiesis by directly repressing critical erythroid lineage specifiers.
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    Nanog regulates Pou3f1 expression at the exit from pluripotency during gastrulation
    (The Company of Biologists, 2019-12) Barral, Antonio; Rollan, Isabel; Sanchez-Iranzo, Hector; Jawaid, Wajid; Badia-Careaga, Claudio; Menchero, Sergio; Gomez, Manuel J; Torroja, Carlos; Sanchez-Cabo, Fatima; Göttgens, Berthold; Manzanares, Miguel; Sainz de Aja, Julio; Ministerio de Ciencia, Innovación y Universidades (España); Wellcome Trust; Instituto de Salud Carlos III; Fundación ProCNIC
    Pluripotency is regulated by a network of transcription factors that maintain early embryonic cells in an undifferentiated state while allowing them to proliferate. NANOG is a critical factor for maintaining pluripotency and its role in primordial germ cell differentiation has been well described. However, Nanog is expressed during gastrulation across all the posterior epiblast, and only later in development is its expression restricted to primordial germ cells. In this work, we unveiled a previously unknown mechanism by which Nanog specifically represses genes involved in anterior epiblast lineage. Analysis of transcriptional data from both embryonic stem cells and gastrulating mouse embryos revealed Pou3f1 expression to be negatively correlated with that of Nanog during the early stages of differentiation. We have functionally demonstrated Pou3f1 to be a direct target of NANOG by using a dual transgene system for the controlled expression of Nanog Use of Nanog null ES cells further demonstrated a role for Nanog in repressing a subset of anterior neural genes. Deletion of a NANOG binding site (BS) located nine kilobases downstream of the transcription start site of Pou3f1 revealed this BS to have a specific role in the regionalization of the expression of this gene in the embryo. Our results indicate an active role of Nanog inhibiting neural regulatory networks by repressing Pou3f1 at the onset of gastrulation.This article has an associated First Person interview with the joint first authors of the paper.
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    Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP
    (BioMed Central (BMC), 2015) Aguirre, Luis A.; Alonso, M. Eva; Badia-Careaga, Claudio; Rollan, Isabel; Arias, Cristina; Fernandez-Minan, Ana; Lopez-Jimenez, Elena; Aranega, Amelia; Gomez-Skarmeta, Jose Luis; Franco, Diego; Manzanares, Miguel; Ministerio de Economía, Industria y Competitividad (España); Comunidad de Madrid (España); Regional Government of Andalusia (España); Fundación ProCNIC
    Background: Recent genome-wide association studies have uncovered genomic loci that underlie an increased risk for atrial fibrillation, the major cardiac arrhythmia in humans. The most significant locus is located in a gene desert at 4q25, approximately 170 kilobases upstream of PITX2, which codes for a transcription factor involved in embryonic left-right asymmetry and cardiac development. However, how this genomic region functionally and structurally relates to PITX2 and atrial fibrillation is unknown. Results: To characterise its function, we tested genomic fragments from 4q25 for transcriptional activity in a mouse atrial cardiomyocyte cell line and in transgenic mouse embryos, identifying a non-tissue-specific potentiator regulatory element. Chromosome conformation capture revealed that this region physically interacts with the promoter of the cardiac specific isoform of Pitx2. Surprisingly, this regulatory region also interacts with the promoter of the next neighbouring gene, Enpep, which we show to be expressed in regions of the developing mouse heart essential for cardiac electrical activity. Conclusions: Our data suggest that de-regulation of both PITX2 and ENPEP could contribute to an increased risk of atrial fibrillation in carriers of disease-associated variants, and show the challenges that we face in the functional analysis of genome-wide disease associations.
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    Essential Roles of Cohesin STAG2 in Mouse Embryonic Development and Adult Tissue Homeostasis.
    (Cell Press, 2020-08-11) De Koninck, Magali; Lapi, Eleonora; Badia-Careaga, Claudio; Cossio, Itziar; Giménez-Llorente, Daniel; Rodríguez-Corsino, Miriam; Andrada, Elena; Hidalgo, Andres; Manzanares, Miguel; Real, Francisco X; Losada, Ana; Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Fundación ProCNIC
    Cohesin mediates sister chromatid cohesion and 3D genome folding. Two versions of the complex carrying STAG1 or STAG2 coexist in somatic vertebrate cells. STAG2 is commonly mutated in cancer, and germline mutations have been identified in cohesinopathy patients. To better understand the underlying pathogenic mechanisms, we report the consequences of Stag2 ablation in mice. STAG2 is largely dispensable in adults, and its tissue-wide inactivation does not lead to tumors but reduces fitness and affects both hematopoiesis and intestinal homeostasis. STAG2 is also dispensable for murine embryonic fibroblasts in vitro. In contrast, Stag2-null embryos die by mid-gestation and show global developmental delay and defective heart morphogenesis, most prominently in structures derived from secondary heart field progenitors. Both decreased proliferation and altered transcription of tissue-specific genes contribute to these defects. Our results provide compelling evidence on cell- and tissue-specific roles of different cohesin complexes and how their dysfunction contributes to disease.
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    Pluripotency factors regulate the onset of Hox cluster activation in the early embryo.
    (American Association for the Advancement of Science (AAAS), 2022-07-15) Tiana, María; Lopez-Jimenez, Elena; Sainz de Aja, Julio; Barral, Antonio; Victorino, Jesus; Badia-Careaga, Claudio; Rollan, Isabel; Rouco, Raquel; Santos, Elisa; Sanchez-Iranzo, Hector; Acemel, Rafael D; Torroja, Carlos; Adan, Javier; Andrés-León, Eduardo; Gomez-Skarmeta, Jose Luis; Giovinazzo, Giovanna; Sanchez-Cabo, Fatima; Manzanares, Miguel; Ministerio de Ciencia e Innovación (España); Gobierno de Andalucía (España); Unión Europea. Comisión Europea. European Research Council (ERC); Fundación La Caixa; Ministerio de Ciencia e Innovación. Unidades de Excelencia María de Maeztu; Fundación Ramón Areces; Instituto de Salud Carlos III; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
    Pluripotent cells are a transient population of the mammalian embryo dependent on transcription factors, such as OCT4 and NANOG, which maintain pluripotency while suppressing lineage specification. However, these factors are also expressed during early phases of differentiation, and their role in the transition from pluripotency to lineage specification is largely unknown. We found that pluripotency factors play a dual role in regulating key lineage specifiers, initially repressing their expression and later being required for their proper activation. We show that Oct4 is necessary for activation of HoxB genes during differentiation of embryonic stem cells and in the embryo. In addition, we show that the HoxB cluster is coordinately regulated by OCT4 binding sites located at the 3' end of the cluster. Our results show that core pluripotency factors are not limited to maintaining the precommitted epiblast but are also necessary for the proper deployment of subsequent developmental programs.
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    CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart
    (Public Library of Science (PLOS), 2017) Gomez-Velazquez, Melisa; Badia-Careaga, Claudio; Lechuga-Vieco, Ana V.; Nieto-Arellano, Rocio; Tena, Juan J.; Rollan, Isabel; Alvarez, Alba; Torroja, Carlos; Caceres, Eva F.; Roy, Anna; Galjart, Niels; Delgado-Olguin, Paul; Sanchez-Cabo, Fatima; Enriquez, Jose Antonio; Luis Gomez-Skarmeta, Jose; Manzanares, Miguel; Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España); Regional Government of Andalusia (España); Pablo de Olavide University (España); Heart and Stroke Foundation (Canadá); Operational Funds from the Hospital for Sick Children; Natural Sciences and Engineering Research Council (Canada); Canadian Institutes of Health Research; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
    Cardiac progenitors are specified early in development and progressively differentiate and mature into fully functional cardiomyocytes. This process is controlled by an extensively studied transcriptional program. However, the regulatory events coordinating the progression of such program from development to maturation are largely unknown. Here, we show that the genome organizer CTCF is essential for cardiogenesis and that it mediates genomic interactions to coordinate cardiomyocyte differentiation and maturation in the developing heart. Inactivation of Ctcf in cardiac progenitor cells and their derivatives in vivo during development caused severe cardiac defects and death at embryonic day 12.5. Genome wide expression analysis in Ctcf mutant hearts revealed that genes controlling mitochondrial function and protein production, required for cardiomyocyte maturation, were upregulated. However, mitochondria from mutant cardiomyocytes do not mature properly. In contrast, multiple development regulatory genes near predicted heart enhancers, including genes in the IrxA cluster, were downregulated in Ctcf mutants, suggesting that CTCF promotes cardiomyocyte differentiation by facilitating enhancer-promoter interactions. Accordingly, loss of CTCF disrupts gene expression and chromatin interactions as shown by chromatin conformation capture followed by deep sequencing. Furthermore, CRISPR-mediated deletion of an intergenic CTCF site within the IrxA cluster alters gene expression in the developing heart. Thus, CTCF mediates local regulatory interactions to coordinate transcriptional programs controlling transitions in morphology and function during heart development.