RESUMEN
The nuclear membrane has an important role for the dynamic regulation of the genome, besides the well-established cytoskeletal function. The nuclear lamina is emerging as an important player in the organization of the position and functional state of interphase chromosomes. Epigenetic modifications such as DNA methylation and histone modifications are required for genome reprogramming during development, tissue-specific gene expression and global gene silencing. The Methyl-CpG binding protein MeCP2 binds methyl-CpG dinucleotides in the mammalian genome and functions as a transcriptional repressor in vivo by interacting with Sin3A, thereby recruiting histone deacetylases (HDAC). MeCP2 also mediates the formation of higher-order chromatin structures contributing to determine the architectural organization of the nucleus. In this paper, we show that MeCP2 interacts in vitro and in vivo with the inner nuclear membrane protein LBR and that the unstructured aminoacidic sequence linking the MBD and TRD domains of MeCP2 is responsible for this association. The formation of an LBR-MeCP2 protein complex might help providing a molecular explanation to the distribution of part of the heterochromatin at the nuclear periphery linked to inner membrane.
Asunto(s)
Heterocromatina/metabolismo , Proteína 2 de Unión a Metil-CpG/metabolismo , Membrana Nuclear/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Secuencia de Bases , Cartilla de ADN/genética , Epigénesis Genética , Prueba de Complementación Genética , Células HeLa , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Proteína 2 de Unión a Metil-CpG/química , Proteína 2 de Unión a Metil-CpG/genética , Microscopía Confocal , Complejos Multiproteicos , Dominios y Motivos de Interacción de Proteínas , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Eliminación de Secuencia , Transfección , Receptor de Lamina BRESUMEN
BACKGROUND: Home blood pressure telemonitoring figures among the possible solutions that could help improve blood pressure control of hypertensive patients. To summarize the effectiveness of home blood pressure telemonitoring on blood pressure control from randomized, controlled studies. METHODS: Electronic databases were searched for publications in English, reporting on randomized trials of home blood pressure telemonitoring vs. usual care. Outcome measures were office or ambulatory blood pressure changes, rate of blood pressure control, and number of antihypertensive drugs used by patients. A random effects model was applied. RESULTS: Twelve studies met inclusion criteria. A high level of heterogeneity was found among studies for all the variables explored. Office blood pressure was reduced significantly more in patients randomized to home telemonitoring (systolic: 5.64 (95% confidence interval: 7.92, 3.36) mm Hg; diastolic: 2.78 (3.93, 1.62) mm Hg; 11 comparisons, n = 4,389). The effect on ambulatory blood pressure was smaller than on office blood pressure (systolic: 2.28 (4.32, 0.24); diastolic: 1.38 (3.55, +0.79) mm Hg; 3 comparisons, n = 655). The relative risk of blood pressure normalization (<140/90 mm Hg nondiabetics and <130/80 mm Hg diabetics) in the telemonitoring vs. the usual care group was 1.31 (1.06, 1.62) (5 comparisons, n = 2,432 subjects). Use of telemonitoring was associated with a significantly increased use of antihypertensive medications (+0.22 (+0.02, +0.43), 5 comparisons, n = 1,991). CONCLUSIONS: Home blood pressure telemonitoring may represent a useful tool to improve blood pressure control. However, heterogeneity of published studies suggests that well designed, large-scale, randomized, controlled studies are still needed to demonstrate the clinical usefulness of this technique.
Asunto(s)
Antihipertensivos/uso terapéutico , Determinación de la Presión Sanguínea/métodos , Monitoreo Ambulatorio de la Presión Arterial , Hipertensión/tratamiento farmacológico , Anciano , Monitoreo Ambulatorio de la Presión Arterial/métodos , Diástole , Femenino , Humanos , Masculino , Persona de Mediana Edad , Visita a Consultorio Médico , Ensayos Clínicos Controlados Aleatorios como Asunto , SístoleRESUMEN
MECP2 is an X-linked gene coding for a protein functioning as a transcriptional repressor. The protein MeCP2 (Methyl CpG-binding protein) is an abundant component of pericentric heterochromatin and its mutations or duplications are present in around 80% of patients with a neurological disorder known as Rett Syndrome. Although MeCP2 action depends critically on its binding to chromatin, very little is known about the dynamics of this process. Using fluorescence recovery after photobleaching in controlled conditions concentration, we demonstrated that most GFP-MeCP2 fusion protein associates strongly and reversibly to pericentric heterocromatin whereas the remaining fraction is bound irreversibly. The mobility of the methyl-binding protein is influenced by the differentiation state of the host cells. Furthermore, residues downstream of the methyl-binding domain are critical for the interaction with chromatin. Whereas the binding is stabilised by the central region it is likely modulated by the most C-terminal region. Importantly, these residues are missing in several disease causing mutations. Our data suggest that alterations in the affinity of MeCP2 for chromatin might contribute to the pathological effects of mutations causing Rett Syndrome.