Transcriptional landscape of a RET C634Y -mutated iPSC and its CRISPR-corrected isogenic control reveals the putative role of EGR1 transcriptional program in the development of multiple endocrine neoplasia type 2A-associated cancers
| Autor: | Roberta Francesca De Rose, Dominique Divers, Olivier Feraud, Christophe Desterke, Annelise Bennaceur-Griscelli, Martin Schlumberger, Frank Griscelli, Mathieu Guibert, Julien Hadoux, Emilie Gobbo, Paule Opolon, Ali G. Turhan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genetics Mutation Context (language use) Cell Biology General Medicine Biology medicine.disease_cause Germline Transcriptome 03 medical and health sciences 030104 developmental biology lcsh:Biology (General) medicine CRISPR Induced pluripotent stem cell Carcinogenesis lcsh:QH301-705.5 Exome sequencing Developmental Biology |
| Zdroj: | Stem Cell Research, Vol 26, Iss, Pp 8-16 (2018) |
| ISSN: | 1873-5061 |
| Popis: | Summary: MEN2A is a hereditary cancer-predisposing syndrome that affects patients with germline RET mutations. The effects of this oncogenic tyrosine kinase in the context of primitive stem cells are not known. In order to study these events, we generated a MEN2A induced Pluripotent Stem Cell (iPSC) line from a patient with RET mutation and an isogenic counterpart by CRISPR-Cas9 correction of the mutation. Whole exome sequencing of iPSC before and after CRISPR-Cas9 genome edition revealed no major exonic off target effect of the CRISPR correction. However, an integrative differential gene expression analysis of iPSC with oncogenic RETC634Y and its gene-corrected iPSC with RETY634C as well as RETwt iPSCs revealed activation of the Early Growth Response 1 (EGR1) transcriptional program in RET-mutated iPSC, a pathway shown to be involved in RET-induced oncogenesis. These data constitute the first proof of concept of the feasibility of the use of an iPSC and its genome-corrected counterpart to unravel the molecular mechanisms underlying the development of the hereditary MEN2A cancer predisposing syndrome. |
| Databáze: | OpenAIRE |
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