Journal
GENOME BIOLOGY
Volume 19, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13059-018-1494-1
Keywords
CRISPR; Functional screen; Enhancers; Oncogene-induced senescence; Gene regulation; AP1; FOS; JUN; FOXF1
Funding
- ERC-AdG enhReg [322493]
- ERC-ITN RNA TRAIN [607720]
- China Scholarship Council (CSC)
- Human Frontier Science Program [LT000640/2013]
- Dutch Organization for Research NWO-TOP [91216002]
- Israeli Cancer Association (ICA)
- Marguerite Stolz Research Fellowship Fund
- Gad
- Nava
- Shye Shtacher fellowship
- European Research Council (ERC) [322493] Funding Source: European Research Council (ERC)
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Background: Functional characterization of non-coding elements in the human genome is a major genomic challenge and the maturation of genome-editing technologies is revolutionizing our ability to achieve this task. Oncogene-induced senescence, a cellular state of irreversible proliferation arrest that is enforced following excessive oncogenic activity, is a major barrier against cancer transformation; therefore, bypassing oncogene-induced senescence is a critical step in tumorigenesis. Here, we aim at further identification of enhancer elements that are required for the establishment of this state. Results: We first apply genome-wide profiling of enhancer-RNAs (eRNAs) to systematically identify enhancers that are activated upon oncogenic stress. DNA motif analysis of these enhancers indicates AP-1 as a major regulator of the transcriptional program induced by oncogene-induced senescence. We thus constructed a CRISPR-Cas9 sgRNA library designed to target senescence-induced enhancers that are putatively regulated by AP-1 and used it in a functional screen. We identify a critical enhancer that we nameEnh(AP1-)(OlS1) and validate that mutating the AP-1 binding site within this element results in oncogene-induced senescence bypass. Furthermore, we identify FOXF1 as the gene regulated by this enhancer and demonstrate that FOXF1 mediates Enh(AP1-)(OlS1) effect on the senescence phenotype. Conclusions: Our study elucidates a novel cascade mediated by AP-1 and FOXF1 that regulates oncogene-induced senescence and further demonstrates the power of CRISPR-based functional genomic screens in deciphering the function of non-coding regulatory elements in the genome.
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