VHL inactivation without hypoxia is sufficient to achieve genome hypermethylation.
Sci Rep
; 8(1): 10667, 2018 Jul 13.
Article
em En
| MEDLINE
| ID: mdl-30006568
ABSTRACT
VHL inactivation is a key oncogenic event for renal carcinomas. In normoxia, VHL suppresses HIF1a-mediated transcriptional response, which is characteristic to hypoxia. It has previously been shown that hypoxic conditions inhibit TET-dependent hydroxymethylation of cytosines and cause DNA hypermethylation at gene promoters. In this work, we performed VHL inactivation by CRISPR/Cas9 and studied its effects on gene expression and DNA methylation. We showed that even without hypoxia, VHL inactivation leads to hypermethylation of the genome. Hypermethylated cytosines were evenly distributed throughout the genome with a slight preference for AP-1 (JUN and FOS) binding sites. Hypermethylated cytosines tended to be enriched within the binding sites of transcription factors that showed increased gene expression after VHL inactivation. We also observed promoter hypermethylation associated with decreased gene expression for several regulators of transcription and DNA methylation including SALL3.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Renais
/
Regulação Neoplásica da Expressão Gênica
/
Metilação de DNA
/
Proteína Supressora de Tumor Von Hippel-Lindau
/
Neoplasias Renais
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article