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Nested epistasis enhancer networks for robust genome regulation.
- Source :
-
Science . 9/2/2022, Vol. 377 Issue 6610, p1077-1085. 9p. 6 Color Photographs. - Publication Year :
- 2022
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00368075
- Volume :
- 377
- Issue :
- 6610
- Database :
- Academic Search Index
- Journal :
- Science
- Publication Type :
- Academic Journal
- Accession number :
- 158831920
- Full Text :
- https://doi.org/10.1126/science.abk3512