Chromatin remodeling: recruitment of histone demethylase RBP2 by Mad1 for transcriptional repression of a Myc target gene, telomerase reverse transcriptase.
FASEB J
; 24(2): 579-86, 2010 Feb.
Article
em En
| MEDLINE
| ID: mdl-19762557
ABSTRACT
The Myc/Max/Mad network transcription factors are known to govern target gene expression through recruiting histone acetyltransferases or deacetylases. In the present study, we show that Mad1 recruits the histone demethylase RBP2 to the Myc target telomerase reverse transcriptase (hTERT) gene promoter to repress transcription. With differentiation of leukemic HL60 cells, Mad1 and RBP2 were both up-regulated, interacted, and cooccupied the hTERT promoter accompanied by histone H3-K4 demethylation. In immortalized p493-6 B cells, shutting down c-Myc led to the accumulation of Mad1 and RBP2 at hTERT promoter and diminished hTERT mRNA expression. When RBP2 was depleted, hTERT expression was significantly enhanced, coupled with dissociation of RBP2 with and increased H3-K4 methylation at the hTERT promoter in p493-6 cells. Moreover, RBP2 and Mad1 were present on the hTERT promoter in human fibroblasts having a silent hTERT gene, and RBP2 depletion resulted in gene derepression. Taken together, Mad1 recruits RBP2 to the hTERT promoter that, in turn, demethylates H3-K4, thereby contributing to a stable repression of the hTERT gene in normal or differentiated malignant cells. Our findings reveal a novel mechanism through which the Myc/Max/Mad network proteins control their target gene transcription and provide insights into mechanisms underlying telomerase silencing and activation.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
/
Proteínas de Ciclo Celular
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Telomerase
/
Montagem e Desmontagem da Cromatina
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Histona Desmetilases
/
Proteína 2 de Ligação ao Retinoblastoma
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article