Sustained expression of FMR1 mRNA from reactivated fragile X syndrome alleles after treatment with small molecules that prevent trimethylation of H3K27.
Hum Mol Genet
; 25(17): 3689-3698, 2016 09 01.
Article
em En
| MEDLINE
| ID: mdl-27378697
ABSTRACT
Expansion of a CGG-repeat tract in the 5'-untranslated region of the FMR1 gene to >200 repeats results in epigenetic silencing of the gene by a mechanism that is still unknown. FMR1 gene silencing results in fragile X syndrome (FXS), the most common heritable cause of intellectual disability. We have previously shown that reactivation of the FMR1 gene in FXS cells with 5-azadeoxycytidine (AZA) leads to the transient recruitment of EZH2, the polycomb repressive complex 2 (PRC2) component responsible for H3K27 trimethylation, and that this recruitment depends on the presence of the FMR1 transcript. However, whether H3K27 trimethylation was essential for FMR1 re-silencing was not known. We show here that EZH2 inhibitors increased FMR1 expression and significantly delayed re-silencing of the FMR1 gene in AZA-treated FXS cells. This delay occurred despite the fact that EZH2 inhibition did not prevent the return of DNA methylation. Treatment with compound 1a, a small molecule that targets CGG-repeats in the FMR1 mRNA, also resulted in sustained expression of the FMR1 gene in AZA-treated cells. This effect of 1a was also associated with a decrease in the levels of H3K27 trimethylation but not DNA methylation. Thus, our data show that EZH2 plays a critical role in the FMR1 gene silencing process and that its inhibition can prolong expression of the FMR1 gene even in the presence of its transcript.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Azacitidina
/
Histonas
/
Proteína do X Frágil da Deficiência Intelectual
/
Bibliotecas de Moléculas Pequenas
/
Proteína Potenciadora do Homólogo 2 de Zeste
Limite:
Humans
/
Male
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article