Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma.
Cell Rep
; 25(13): 3693-3705.e6, 2018 12 26.
Article
em En
| MEDLINE
| ID: mdl-30590042
ABSTRACT
The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth and/or proliferation genes and BETs disproportionately at enhancer-regulated tissue-specific genes. These two separate gene regulatory axes can be simultaneously targeted to impair the myeloma proliferative program, providing an important molecular mechanism for combination therapy. This study therefore suggests a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
1_ASSA2030
Problema de saúde:
1_doencas_nao_transmissiveis
Assunto principal:
Regulação Neoplásica da Expressão Gênica
/
Elementos Facilitadores Genéticos
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Regiões Promotoras Genéticas
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Transcriptoma
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Mieloma Múltiplo
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos