RESUMEN
Juvenile animals possess distinct properties that are missing in adults. These properties include capabilities for higher growth, faster wound healing, plasticity and regeneration. However, the molecular mechanisms underlying these juvenile physiological properties are not fully understood. To obtain insight into the distinctiveness of juveniles from adults at the molecular level, we assessed long noncoding RNAs (lncRNAs) that are highly expressed selectively in juvenile cells. The noncoding elements of the transcriptome were investigated in hepatocytes and cardiomyocytes isolated from juvenile and adult mice. Here, we identified 62 juvenility-associated lncRNAs (JAlncs), which are selectively expressed in both hepatocytes and cardiomyocytes from juvenile mice. Among these common (shared) JAlncs, Gm14230 is evolutionarily conserved and is essential for cellular juvenescence. Loss of Gm14230 impairs cell growth and causes cellular senescence. Gm14230 safeguards cellular juvenescence through recruiting the histone methyltransferase Ezh2 to Tgif2, thereby repressing the functional role of Tgif2 in cellular senescence. Thus, we identify Gm14230 as a juvenility-selective lncRNA required to maintain cellular juvenescence.
Asunto(s)
Envejecimiento/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteínas de Homeodominio/metabolismo , ARN Largo no Codificante/genética , Proteínas Represoras/metabolismo , Animales , Ciclo Celular , Proteína Potenciadora del Homólogo Zeste 2/genética , Regulación de la Expresión Génica , Hepatocitos/citología , Proteínas de Homeodominio/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/citología , Células 3T3 NIH , Proteínas Represoras/genética , Transcriptoma , TransfecciónRESUMEN
It is not fully understood how enzymes are regulated in the tiny reaction field of a cell. Several enzymatic proteins form cytoophidia, a cellular macrostructure to titrate enzymatic activities. Here, we show that the epileptic encephalopathy-associated protein Tbc1d24 forms cytoophidia in neuronal cells both in vitro and in vivo. The Tbc1d24 cytoophidia are distinct from previously reported cytoophidia consisting of inosine monophosphate dehydrogenase (Impdh) or cytidine-5'-triphosphate synthase (Ctps). Tbc1d24 cytoophidia is induced by loss of cellular juvenescence caused by depletion of Gm14230, a juvenility-associated lncRNA (JALNC) and zeocin treatment. Cytoophidia formation is associated with impaired enzymatic activity of Tbc1d24. Thus, our findings reveal the property of Tbc1d24 to form cytoophidia to maintain neuronal cellular juvenescence.
Asunto(s)
Encéfalo/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Neuronas/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Encéfalo/citología , Línea Celular , Células Cultivadas , Proteínas Activadoras de GTPasa/genética , Regulación de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Neuronas/citología , ARN Largo no Codificante/genéticaRESUMEN
The juvenile phase is characterized by continuously progressing physiological processes such as growth and maturation, which are accompanied by transitions in gene expression. The contribution of transcriptome dynamics to the establishment of juvenile properties remains unclear. Here, we investigated alternative splicing (AS) events in postnatal growth and elucidated the landscape of age-dependent alternative splicing (ADAS) in C57BL/6 mice. Our analysis of ADAS in the cerebral cortex, cardiomyocytes, and hepatocytes revealed numerous juvenile-specific splicing isoforms that shape the juvenile transcriptome, which in turn functions as a basis for the highly anabolic status of juvenile cells. Mechanistically, the juvenile-expressed splicing factor Srsf7 mediates ADAS, as exemplified by switching from juvenile to adult forms of anabolism-associated genes Eif4a2 and Rbm7. Suppression of Srsf7 results in "fast-forwarding" of this transcriptome transition, causing impaired anabolism and growth in mice. Thus, juvenile-specific AS is indispensable for the anabolic state of juveniles and differentiates juveniles from adults.