CRISPR/dCas9-mediated DNA demethylation screen identifies driver epigenetic determinants of colorectal cancer (Processed data)
Rattachement africain : es, us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Background: Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this epigenetic mechanism is an actual driver of cancer or is a mere consequence of the carcinogenic process remains to be elucidated. Results: In this work we performed an integrative multi -omic approach to identify gene candidates with strong correlations between DNA methylation and gene expression in human CRC samples and a set of 8 colon cancer cell lines. As a proof of concept, we combined recent CRISPR-Cas9 epigenome editing tools (dCas9-TET1, dCas9-TET-IM) with a custom arrayed gRNA library to modulate the DNA methylation status of 56 promoters previously linked with strong epigenetic repression in CRC, and we monitored the potential functional consequences of such DNA methylation loss by means of a high-content cell proliferation screen. Overall, the epigenetic modulation of most of these DNA methylated regions had a mild impact in the reactivation of gene expression and in the viability of cancer cells. Interestingly, we found that epigenetic reactivation of RSPO2 in the tumour context was associated with a significant impairment in cell proliferation in p53-/- cancer cell lines and further validation with human samples demonstrated that the epigenetic silencing of RSPO2 is a mid-late event in the adenoma to carcinoma sequence. Conclusions: These results highlight the potential role of DNA methylation as a driver mechanism of CRC and open up the venue for the identification of novel therapeutic windows based on the epigenetic reactivation of certain tumour suppressor genes.
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Où se fait cette recherche
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Nanomaterials and Nanotechnology Research Center pays non établi dans la noticeStructure de recherche
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Universidad de Oviedo pays non établi dans la noticeUniversité ou école supérieure
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Instituto de Investigación Sanitaria del Principado de Asturias pays non établi dans la noticeStructure de recherche
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Instituto Maimónides de Investigación Biomédica de Córdoba pays non établi dans la noticeStructure de recherche
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Biomedical Research Institute pays non établi dans la noticeOrganisation à but non lucratif
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Hospital Universitario Central de Asturias pays non établi dans la noticeÉtablissement de santé
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Health Research Institute of the Principality of Asturias (ISPA) pays non établi dans la noticeStructure de recherche
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University of Oviedo pays non établi dans la noticeUniversité ou école supérieure
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Institute of Oncology of Asturias (IUOPA) pays non établi dans la noticeStructure de recherche
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Central University Hospital of Asturias (HUCA) pays non établi dans la noticeUniversité ou école supérieure
Nanomaterials and Nanotechnology Research Center, Universidad de Oviedo et Instituto de Investigación Sanitaria del Principado de Asturias, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.