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1.
Mol Cell ; 80(4): 726-735.e7, 2020 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-33049227

RESUMEN

Diffuse midline gliomas and posterior fossa type A ependymomas contain the recurrent histone H3 lysine 27 (H3 K27M) mutation and express the H3 K27M-mimic EZHIP (CXorf67), respectively. H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity. In vivo, these proteins reduce overall H3 lysine 27 trimethylation (H3K27me3) levels; however, residual peaks of H3K27me3 remain at CpG islands (CGIs) through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with PRC2 that is allosterically activated by H3K27me3 at CGIs and impede its spreading. Moreover, H3 K27M oncohistones reduce H3K27me3 in trans, independent of their incorporation into the chromatin. Although EZHIP is not found outside placental mammals, expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved mechanism. Our results provide mechanistic insights for the retention of residual H3K27me3 in tumors driven by H3 K27M and EZHIP.


Asunto(s)
Cromatina/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Mutación , Proteínas Oncogénicas/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Regulación Alostérica , Animales , Islas de CpG , Drosophila melanogaster , Humanos , Ratones , Proteínas Oncogénicas/genética , Complejo Represivo Polycomb 2/genética
2.
G3 (Bethesda) ; 12(9)2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-35876878

RESUMEN

Following fertilization, the unified germ cells rapidly transition to a totipotent embryo. Maternally deposited mRNAs encode the proteins necessary for this reprogramming as the zygotic genome remains transcriptionally quiescent during the initial stages of development. The transcription factors required to activate the zygotic genome are among these maternally deposited mRNAs and are robustly translated following fertilization. In Drosophila, the mRNA encoding Zelda, the major activator of the zygotic genome, is not translated until 1 h after fertilization. Here we demonstrate that zelda translation is repressed in the early embryo by the TRIM-NHL protein Brain tumor (BRAT). BRAT also regulates Zelda levels in the larval neuroblast lineage. In the embryo, BRAT-mediated translational repression is regulated by the Pan Gu kinase, which is triggered by egg activation. The Pan Gu kinase phosphorylates translational regulators, suggesting that Pan Gu kinase activity alleviates translational repression of zelda by BRAT and coupling translation of zelda with that of other regulators of early embryonic development. Using the premature translation of zelda in embryos lacking BRAT activity, we showed that early translation of a zygotic genome activator is not sufficient to drive precocious gene expression. Instead, Zelda-target genes showed increased expression at the time they are normally activated. We propose that transition through early development requires the integration of multiple processes, including the slowing of the nuclear division cycle and activation of the zygotic genome. These processes are coordinately controlled by Pan Gu kinase-mediated regulation of translation.


Asunto(s)
Proteínas de Drosophila , Drosophila , Animales , Proteínas de Unión al ADN/genética , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Proteínas Nucleares/genética , ARN Mensajero/genética , Activación Transcripcional
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