Person: Badia-Careaga, Claudio
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First Name
Claudio
Last Name
Badia-Careaga
Institution
CNIC
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Publication 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 ProCNICCohesin 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.Publication 4D reconstruction of murine developmental trajectories using spherical harmonics.(Cell Press, 2022-09-12) Dalmasso, Giovanni; Musy, Marco; Niksic, Martina; Robert-Moreno, Alexandre; Badia-Careaga, Claudio; Sanz-Ezquerro, Juan Jose; Sharpe, James; European Molecular Biology Laboratory; Unión Europea. Comisión Europea. European Research Council (ERC); Fundación La Marató TV3Normal organogenesis cannot be recapitulated in vitro for mammalian organs, unlike in species including Drosophila and zebrafish. Available 3D data in the form of ex vivo images only provide discrete snapshots of the development of an organ morphology. Here, we propose a computer-based approach to recreate its continuous evolution in time and space from a set of 3D volumetric images. Our method is based on the remapping of shape data into the space of the coefficients of a spherical harmonics expansion where a smooth interpolation over time is simpler. We tested our approach on mouse limb buds and embryonic hearts. A key advantage of this method is that the resulting 4D trajectory can take advantage of all the available data while also being able to interpolate well through time intervals for which there are little or no data. This allows for a quantitative, data-driven 4D description of mouse limb morphogenesis.Publication Basal oxidation of conserved cysteines modulates cardiac titin stiffness and dynamics(Elsevier, 2022-03-28) Herrero-Galan, Elas; Martinez-Martin, Ines; Sanchez-Gonzalez, Cristina; Vicente, Natalia; Bonzon-Kulichenko, Elena; Calvo, Enrique; Suay-Corredera, Carmen; Pricolo, Maria Rosaria; Fernández-Trasancos, Ángel; Velázquez-Carreras, Diana; Badia-Careaga, Claudio; Abdellatif, Mahmoud; Sedej, Simon; Rainer, Peter P.; Giganti, David; Pérez-Jiménez, Raúl; Vazquez, Jesus; Alegre-Cebollada, Jorge; Ministerio de Ciencia e Innovación (España); Comunidad de Madrid (España); Instituto de Salud Carlos III; Fundación La Caixa; FWF Austrian Science Fund; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Titin, as the main protein responsible for the passive stiffness of the sarcomere, plays a key role in diastolic function and is a determinant factor in the etiology of heart disease. Titin stiffness depends on unfolding and folding transitions of immunoglobulin-like (Ig) domains of the I-band, and recent studies have shown that oxidative modifications of cryptic cysteines belonging to these Ig domains modulate their mechanical properties in vitro. However, the relevance of this mode of titin mechanical modulation in vivo remains largely unknown. Here, we describe the high evolutionary conservation of titin mechanical cysteines and show that they are remarkably oxidized in murine cardiac tissue. Mass spectrometry analyses indicate a similar landscape of basal oxidation in murine and human myocardium. Monte Carlo simulations illustrate how disulfides and S-thiolations on these cysteines increase the dynamics of the protein at physiological forces, while enabling load- and isoform-dependent regulation of titin stiffness. Our results demonstrate the role of conserved cysteines in the modulation of titin mechanical properties in vivo and point to potential redox-based pathomechanisms in heart disease.Publication 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 ProCNICCohesin 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.Publication 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.