RESUMEN
Liver development proceeds by sequential steps during which gene regulatory networks (GRNs) determine differentiation and maturation of hepatic cells. Characterizing the architecture and dynamics of these networks is essential for understanding how cell fate decisions are made during development, and for recapitulating these processes during in vitro production of liver cells for toxicology studies, disease modelling and regenerative therapy. Here we review the GRNs that control key steps of liver development and lead to differentiation of hepatocytes and cholangiocytes in mammals. We focus on GRNs determining cell fate decisions and analyse subcircuitry motifs that may confer specific dynamic properties to the networks. Finally, we put our analysis in the perspective of recent attempts to directly reprogram cells to hepatocytes by forced expression of transcription factors.
Asunto(s)
Reprogramación Celular/genética , Redes Reguladoras de Genes/genética , Hepatocitos/metabolismo , Animales , Diferenciación Celular , HumanosRESUMEN
HOX proteins define a family of key transcription factors regulating animal embryogenesis. HOX genes have also been linked to oncogenesis and HOXA1 has been described to be active in several cancers, including breast cancer. Through a proteome-wide interaction screening, we previously identified the TNFR-associated proteins RBCK1/HOIL-1 and TRAF2 as HOXA1 interactors suggesting that HOXA1 is functionally linked to the TNF/NF-κB signaling pathway. Here, we reveal a strong positive correlation between expression of HOXA1 and of members of the TNF/NF-κB pathway in breast tumor datasets. Functionally, we demonstrate that HOXA1 can activate NF-κB and operates upstream of the NF-κB inhibitor IκB. Consistently, we next demonstrate that the HOXA1-mediated activation of NF-κB is non-transcriptional and that RBCK1 and TRAF2 influences on NF-κB are epistatic to HOXA1. We also identify an 11 Histidine repeat and the homeodomain of HOXA1 to be required both for RBCK1 and TRAF2 interaction and NF-κB stimulation. Finally, we highlight that activation of NF-κB is crucial for HOXA1 oncogenic activity.
Asunto(s)
Proteínas de Homeodominio/metabolismo , FN-kappa B/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Factores de Transcripción/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Conjuntos de Datos como Asunto , Epistasis Genética , Regulación Neoplásica de la Expresión Génica , Histidina/metabolismo , Proteínas de Homeodominio/química , Proteínas de Homeodominio/genética , Humanos , Proteínas I-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Unión Proteica/genética , Dominios Proteicos , Eliminación de Secuencia , Factores de Transcripción/química , Factores de Transcripción/genética , Transcripción Genética , TranscriptomaRESUMEN
Osteogenesis imperfecta type III (OI) is a serious genetic condition with poor bone quality and a high fracture rate in children. In a previous study, it was shown that a monoclonal antibody neutralizing sclerostin (Scl-Ab) increases strength and vertebral bone mass while reducing the number of axial fractures in oim/oim, a mouse model of OI type III. Here, we analyze the impact of Scl-Ab on long bones in OI mice. After 9â¯weeks of treatment, Scl-Ab significantly reduced long bone fractures (3.6⯱â¯0.3 versus 2.1⯱â¯0.8 per mouse, pâ¯<â¯0.001). In addition, the cortical thickness of the tibial midshaft was increased (+42%, pâ¯<â¯0.001), as well as BMD (+28%, pâ¯<â¯0.001), ultimate load (+86%, pâ¯<â¯0.05), plastic energy (+184%; pâ¯<â¯0.05) and stiffness (+172%; pâ¯<â¯0.01) in OI Scl-Ab mice compared to OI vehicle controls. Similar effects of Scl-Ab were observed in Wild type (Wt) mice. The plastic energy, which reflects the fragility of the tissue, was lower in the OI than in the Wt and significantly improved with the Scl-Ab treatment. At the tissue level by nanoindentation, Scl-Ab slightly increased the elastic modulus in bones of both OI and Wt, while moderately increasing tissue hardness (+13% compared to the vehicle; pâ¯<â¯0.05) in Wt bones, but not in OI bones. Although it did not change the properties of the OI bone matrix material, Scl-Ab reduced the fracture rate of the long bones by improving its bone mass, density, geometry, and biomechanical strength. These results suggest that Scl-Ab can reduce long-bone fractures in patients with OI.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Anticuerpos/uso terapéutico , Fracturas Óseas/complicaciones , Fracturas Óseas/tratamiento farmacológico , Osteogénesis Imperfecta/complicaciones , Animales , Anticuerpos/farmacología , Fenómenos Biomecánicos , Densidad Ósea/efectos de los fármacos , Diáfisis/efectos de los fármacos , Diáfisis/fisiopatología , Modelos Animales de Enfermedad , Femenino , Fémur/efectos de los fármacos , Fémur/fisiopatología , Fracturas Óseas/fisiopatología , Masculino , Ratones , Análisis de Supervivencia , Tibia/efectos de los fármacos , Tibia/fisiopatologíaRESUMEN
Understanding how the activity of transcription factors like HOX proteins is regulated remains a widely open question. In a recent screen for proteins interacting with HOXA1, we identified a PRDM protein family member, PRDM14, which is known to be transiently co-expressed with HOXA1 in epiblast cells before their specification towards somatic versus germ cell fate. Here, we confirm PRDM14 is an interactor of HOXA1 and we identify the homeodomain of HOXA1 as well as the PR domain and Zinc fingers of PRDM14 to be required for the interaction. An 11-His repeat of HOXA1 previously highlighted to contribute to HOXA1-mediated protein-protein interactions is also involved. At a functional level, we provide evidence that HOXA1 displays an unexpectedly long half-life and demonstrate that PRDM14 can reduce the stability and affect the transcriptional activity of HOXA1.