Nested epistasis enhancer networks for robust genome regulation.
Science
; 377(6610): 1077-1085, 2022 09 02.
Article
en En
| MEDLINE
| ID: mdl-35951677
ABSTRACT
Mammalian genomes have multiple enhancers spanning an ultralong distance (>megabases) to modulate important genes, but it is unclear how these enhancers coordinate to achieve this task. We combine multiplexed CRISPRi screening with machine learning to define quantitative enhancer-enhancer interactions. We find that the ultralong distance enhancer network has a nested multilayer architecture that confers functional robustness of gene expression. Experimental characterization reveals that enhancer epistasis is maintained by three-dimensional chromosomal interactions and BRD4 condensation. Machine learning prediction of synergistic enhancers provides an effective strategy to identify noncoding variant pairs associated with pathogenic genes in diseases beyond genome-wide association studies analysis. Our work unveils nested epistasis enhancer networks, which can better explain enhancer functions within cells and in diseases.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad
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Elementos de Facilitación Genéticos
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Epistasis Genética
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Aprendizaje Automático
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article