دورية أكاديمية
Mismatch repair-signature mutations activate gene enhancers across human colorectal cancer epigenomes
| العنوان: | Mismatch repair-signature mutations activate gene enhancers across human colorectal cancer epigenomes |
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| المؤلفون: | Hung, Stevephen, Saiakhova, Alina, Faber, Zachary J, Bartels, Cynthia F, Neu, Devin, Bayles, Ian, Ojo, Evelyn, Hong, Ellen S, Pontius, W Dean, Morton, Andrew R, Liu, Ruifu, Kalady, Matthew F, Wald, David N, Markowitz, Sanford, Scacheri, Peter C |
| المساهمون: | National Institutes of Health, Case Western Reserve University |
| المصدر: | eLife ; volume 8 ; ISSN 2050-084X |
| بيانات النشر: | eLife Sciences Publications, Ltd |
| سنة النشر: | 2019 |
| المجموعة: | eLife (E-Journal - via CrossRef) |
| الوصف: | Commonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent. The indels affect short homopolymer tracts of A/T and increase affinity for FOX transcription factors. We further demonstrate that signature mismatch-repair (MMR) mutations activate enhancers using a xenograft tumor metastasis model, where mutations are induced naturally via CRISPR/Cas9 inactivation of MLH1 prior to tumor cell injection. Our results suggest that MMR signature mutations activate enhancers in CRC tumor epigenomes to provide a selective advantage. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.7554/elife.40760 |
| الإتاحة: | https://doi.org/10.7554/elife.40760Test https://cdn.elifesciences.org/articles/40760/elife-40760-v1.pdfTest https://cdn.elifesciences.org/articles/40760/elife-40760-v1.xmlTest https://elifesciences.org/articles/40760Test |
| حقوق: | http://creativecommons.org/licenses/by/4.0Test/ ; http://creativecommons.org/licenses/by/4.0Test/ ; http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.663B1E6D |
| قاعدة البيانات: | BASE |
| DOI: | 10.7554/elife.40760 |
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