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1.
EMBO J ; 39(6): e102513, 2020 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-32073171

RESUMEN

Various species of non-coding RNAs (ncRNAs) are enriched in specific subcellular compartments, but the mechanisms orchestrating their localization and their local functions remain largely unknown. We investigated both aspects using the elongating retinal ganglion cell axon and its tip, the growth cone, as models. We reveal that specific endogenous precursor microRNAs (pre-miRNAs) are actively trafficked to distal axons by hitchhiking primarily on late endosomes/lysosomes. Upon exposure to the axon guidance cue semaphorin 3A (Sema3A), pre-miRNAs are processed specifically within axons into newly generated miRNAs, one of which, in turn, silences the basal translation of tubulin beta 3 class III (TUBB3), but not amyloid beta precursor protein (APP). At the organismal level, these mature miRNAs are required for growth cone steering and a fully functional visual system. Overall, our results uncover a novel mode of ncRNA transport from one cytosolic compartment to another within polarized cells. They also reveal that newly generated miRNAs are critical components of a ncRNA-based signaling pathway that transduces environmental signals into the structural remodeling of subcellular compartments.


Asunto(s)
MicroARNs/genética , ARN no Traducido/genética , Transducción de Señal , Animales , Axones/fisiología , Transporte Biológico , Endosomas/metabolismo , Femenino , Conos de Crecimiento/fisiología , Ratones Endogámicos C57BL , Precursores del ARN/genética , Células Ganglionares de la Retina/fisiología , Xenopus laevis
2.
Oncotarget ; 6(7): 4816-28, 2015 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-25693204

RESUMEN

Androgen Receptor (AR) and Estrogen Receptors (ERs) are key nuclear receptors that can cooperate in orchestrating gene expression programs in multiple tissues and diseases, targeting binding elements in promoters and distant enhancers. We report the unbiased identification of enhancer elements bound by AR and ER-α whose activity can be allele-specific depending on the status of nearby Single Nucleotide Polymorphisms (SNP). ENCODE data were computationally mined to nominate genomic loci with: (i) chromatin signature of enhancer activity from activation histone marks, (ii) binding evidence by AR and ER-α, (iii) presence of a SNP. Forty-one loci were identified and two, on 1q21.3 and 13q34, selected for characterization by gene reporter, Chromatin immunoprecipitation (ChIP) and RT-qPCR assays in breast (MCF7) and prostate (PC-3) cancer-derived cell lines. We observed allele-specific enhancer activity, responsiveness to ligand-bound AR, and potentially influence on the transcription of closely located genes (RAB20, ING1, ARHGEF7, ADAM15). The 1q21.3 variant, rs2242193, showed impact on AR binding in MCF7 cells that are heterozygous for the SNP. Our unbiased genome-wide search proved to be an efficient methodology to discover new functional polymorphic regulatory regions (PRR) potentially acting as risk modifiers in hormone-driven cancers and overall nominated SNPs in PRR across 136 transcription factors.


Asunto(s)
Neoplasias de la Mama/genética , Elementos de Facilitación Genéticos/genética , Receptor alfa de Estrógeno/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Alelos , Western Blotting , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Inmunoprecipitación de Cromatina , Simulación por Computador , Receptor alfa de Estrógeno/metabolismo , Femenino , Genoma Humano , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Androgénicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
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