RESUMEN
Histone H3 lysine 9 (H3K9) methylation is a hallmark of heterochromatin. H3K9 demethylation is crucial in mouse sex determination; The H3K9 demethylase Jmjd1a deficiency leads to increased H3K9 methylation at the Sry locus in embryonic gonads, thereby compromising Sry expression and causing male-to-female sex reversal. We hypothesized that the H3K9 methylation level at the Sry locus is finely tuned by the balance in activities between the H3K9 demethylase Jmjd1a and an unidentified H3K9 methyltransferase to ensure correct Sry expression. Here we identified the GLP/G9a H3K9 methyltransferase complex as the enzyme catalyzing H3K9 methylation at the Sry locus. Based on this finding, we tried to rescue the sex-reversal phenotype of Jmjd1a-deficient mice by modulating GLP/G9a complex activity. A heterozygous GLP mutation rescued the sex-reversal phenotype of Jmjd1a-deficient mice by restoring Sry expression. The administration of a chemical inhibitor of GLP/G9a enzyme into Jmjd1a-deficient embryos also successfully rescued sex reversal. Our study not only reveals the molecular mechanism underlying the tuning of Sry expression but also provides proof on the principle of therapeutic strategies based on the pharmacological modulation of epigenetic balance.
Asunto(s)
N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Proteína de la Región Y Determinante del Sexo/metabolismo , Desarrollo Sexual/genética , Animales , Femenino , Regulación de la Expresión Génica , Sitios Genéticos , Gónadas/embriología , Gónadas/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Histonas/genética , Histona Demetilasas con Dominio de Jumonji/deficiencia , Histona Demetilasas con Dominio de Jumonji/metabolismo , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Análisis de Secuencia de ADN , Proteína de la Región Y Determinante del Sexo/genéticaRESUMEN
Functional ceramics with oriented crystals prepared by colloidal processing in a strong magnetic field are expected to show improved functionality. In this study, the orientation rate of particles with low magnetic susceptibility in a concentrated slurry under a strong rotating magnetic field was experimentally demonstrated using a fast photopolymerization reaction. A slurry of (Sr,Ca)2NaNb5O15 particles dispersed in an ultraviolet curable resin with a catalyst was consolidated using UV irradiation under a strong rotating magnetic field. The degree of particle orientation increased with increasing processing time and became saturated after 20 s. The orientation time was observed experimentally; the period required to achieve particle orientation was proportional to the measured viscosity of the slurry and the inverse of the square of the magnetic flux density.