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1.
Nat Commun ; 10(1): 5657, 2019 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-31827083

RESUMEN

MicroRNA (miRNA) biogenesis initiates co-transcriptionally, but how the Microprocessor machinery pinpoints the locations of short precursor miRNA sequences within long flanking regions of the transcript is not known. Here we show that miRNA biogenesis depends on DNA methylation. When the regions flanking the miRNA coding sequence are highly methylated, the miRNAs are more highly expressed, have greater sequence conservation, and are more likely to drive cancer-related phenotypes than miRNAs encoded by unmethylated loci. We show that the removal of DNA methylation from miRNA loci leads to their downregulation. Further, we found that MeCP2 binding to methylated miRNA loci halts RNA polymerase II elongation, leading to enhanced processing of the primary miRNA by Drosha. Taken together, our data reveal that DNA methylation directly affects miRNA biogenesis.


Asunto(s)
MicroARNs/genética , Animales , Línea Celular , Metilación de ADN , Humanos , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , MicroARNs/metabolismo , Sistemas de Lectura Abierta , Procesamiento Postranscripcional del ARN
2.
PLoS One ; 14(3): e0211602, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30889183

RESUMEN

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from a point mutation at the 5' splice site of intron 20 in the IKBKAP gene. This mutation decreases production of the IKAP protein, and treatments that increase the level of the full-length IKBKAP transcript are likely to be of therapeutic value. We previously found that phosphatidylserine (PS), an FDA-approved food supplement, elevates IKAP levels in cells generated from FD patients. Here we demonstrate that combined treatment of cells generated from FD patients with PS and kinetin or PS and the histone deacetylase inhibitor trichostatin A (TSA) resulted in an additive elevation of IKAP compared to each drug alone. This indicates that the compounds influence different pathways. We also found that pridopidine enhances production of IKAP in cells generated from FD patients. Pridopidine has an additive effect on IKAP levels when used in combination with kinetin or TSA, but not with PS; suggesting that PS and pridopidine influence IKBKAP levels through the same mechanism. Indeed, we demonstrate that the effect of PS and pridopidine is through sigma-1 receptor-mediated activation of the BDNF signaling pathway. A combination treatment with any of these drugs with different mechanisms has potential to benefit FD patients.


Asunto(s)
Proteínas Portadoras/metabolismo , Disautonomía Familiar/tratamiento farmacológico , Disautonomía Familiar/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas Portadoras/genética , Células Cultivadas , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Disautonomía Familiar/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Cinetina/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosfatidilserinas/farmacología , Piperidinas/farmacología , Factores de Elongación Transcripcional , Resultado del Tratamiento , Tubulina (Proteína)/metabolismo
3.
PLoS Genet ; 12(12): e1006486, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27997532

RESUMEN

Familial Dysautonomia (FD) is a neurodegenerative disease in which aberrant tissue-specific splicing of IKBKAP exon 20 leads to reduction of IKAP protein levels in neuronal tissues. Here we generated a conditional knockout (CKO) mouse in which exon 20 of IKBKAP is deleted in the nervous system. The CKO FD mice exhibit developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. Furthermore, the CKO FD DRGs show elevated HDAC6 levels, reduced acetylated α-tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF). These abnormalities in DRG properties underlie neuronal degeneration and FD symptoms. Phosphatidylserine treatment decreased HDAC6 levels and thus increased acetylation of α-tubulin. Further PS treatment resulted in recovery of axonal outgrowth and enhanced retrograde axonal transport by decreasing histone deacetylase 6 (HDAC6) levels and thus increasing acetylation of α-tubulin levels. Thus, we have identified the molecular pathway that leads to neurodegeneration in FD and have demonstrated that phosphatidylserine treatment has the potential to slow progression of neurodegeneration.


Asunto(s)
Transporte Axonal/efectos de los fármacos , Disautonomía Familiar/genética , Histona Desacetilasas/genética , Fosfatidilserinas/administración & dosificación , Tubulina (Proteína)/genética , Empalme Alternativo/genética , Animales , Transporte Axonal/genética , Axones/efectos de los fármacos , Modelos Animales de Enfermedad , Disautonomía Familiar/tratamiento farmacológico , Disautonomía Familiar/patología , Exones/genética , Ganglios Espinales/crecimiento & desarrollo , Ganglios Espinales/patología , Histona Desacetilasa 6 , Histona Desacetilasas/biosíntesis , Humanos , Ratones , Ratones Noqueados , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Factor de Crecimiento Nervioso/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fosfatidilserinas/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
4.
Genome Res ; 26(4): 541-53, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26860615

RESUMEN

Splicing aberrations are prominent drivers of cancer, yet the regulatory pathways controlling them are mostly unknown. Here we develop a method that integrates physical interaction, gene expression, and alternative splicing data to construct the largest map of transcriptomic and proteomic interactions leading to cancerous splicing aberrations defined to date, and identify driver pathways therein. We apply our method to colon adenocarcinoma and non-small-cell lung carcinoma. By focusing on colon cancer, we reveal a novel tumor-favoring regulatory pathway involving the induction of the transcription factor MYC by the transcription factor ELK1, as well as the subsequent induction of the alternative splicing factor PTBP1 by both. We show that PTBP1 promotes specific RAC1,NUMB, and PKM splicing isoforms that are major triggers of colon tumorigenesis. By testing the pathway's activity in patient tumor samples, we find ELK1,MYC, and PTBP1 to be overexpressed in conjunction with oncogenic KRAS mutations, and show that these mutations increase ELK1 levels via the RAS-MAPK pathway. We thus illuminate, for the first time, a full regulatory pathway connecting prevalent cancerous mutations to functional tumor-inducing splicing aberrations. Our results demonstrate our method is applicable to different cancers to reveal regulatory pathways promoting splicing aberrations.


Asunto(s)
Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Empalme del ARN , Transducción de Señal , Proteína Elk-1 con Dominio ets/metabolismo , Análisis por Conglomerados , Biología Computacional , Perfilación de la Expresión Génica , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo
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