1. Dnmt3b knock-down in enteric precursors reveals a possible mechanism by which this de novo methyltransferase is involved in the enteric nervous system development and the onset of Hirschsprung disease
- Author
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Raquel M. Fernández, Guillermo Antiñolo, Salud Borrego, María José Moya-Jiménez, Leticia Villalba-Benito, Ana Torroglosa, Instituto de Salud Carlos III, European Commission, Junta de Andalucía, [Torroglosa, Ana] Univ Seville, Univ Hosp Virgen del Rocio, Dept Genet Reprod & Fetal Med, Inst Biomed Seville,CSIC, Seville 41013, Spain, [Villalba-Benito, Leticia] Univ Seville, Univ Hosp Virgen del Rocio, Dept Genet Reprod & Fetal Med, Inst Biomed Seville,CSIC, Seville 41013, Spain, [Maria Fernandez, Raquel] Univ Seville, Univ Hosp Virgen del Rocio, Dept Genet Reprod & Fetal Med, Inst Biomed Seville,CSIC, Seville 41013, Spain, [Antinolo, Guillermo] Univ Seville, Univ Hosp Virgen del Rocio, Dept Genet Reprod & Fetal Med, Inst Biomed Seville,CSIC, Seville 41013, Spain, [Borrego, Salud] Univ Seville, Univ Hosp Virgen del Rocio, Dept Genet Reprod & Fetal Med, Inst Biomed Seville,CSIC, Seville 41013, Spain, [Torroglosa, Ana] Ctr Biomed Network Res Rare Dis, Seville 41013, Spain, [Villalba-Benito, Leticia] Ctr Biomed Network Res Rare Dis, Seville 41013, Spain, [Maria Fernandez, Raquel] Ctr Biomed Network Res Rare Dis, Seville 41013, Spain, [Antinolo, Guillermo] Ctr Biomed Network Res Rare Dis, Seville 41013, Spain, [Borrego, Salud] Ctr Biomed Network Res Rare Dis, Seville 41013, Spain, [Jose Moya-Jimenez, Maria] Univ Hosp Virgen del Rocio, Dept Pediat Surg, Seville 41013, Spain, European Union (ERDF/ESF, 'Investing in your future'), Regional Ministry of Innovation, Science and Enterprise of the Autonomous Government of Andalucia, Universidad de Sevilla. Departamento de Cirugía., and CTS-106: Genética médica en Ciencias de la Salud.
- Subjects
0301 basic medicine ,P21 ,Hirschsprung disease ,DNMT3B ,Apoptosis ,Expression ,Biology ,ENS development ,Methylation ,03 medical and health sciences ,Dna methyltransferases ,Precursor cell ,DNMT3b ,Gene knockdown ,Gastrointestinal tract ,Ret protooncogene ,P53 ,Neural crest development ,Neural crest ,Anatomy ,Cancer-cells ,Embryonic stem-cells ,In vitro ,Cell biology ,030104 developmental biology ,Oncology ,Differentiation ,embryonic structures ,Enteric nervous system ,Signal transduction ,Research Paper - Abstract
Hirschsprung disease (HSCR, OMIM 142623) is a pathology that shows a lack of enteric ganglia along of the distal gastrointestinal tract. This aganglionosis is attributed to an abnormal proliferation, migration, differentiation and/or survival of enteric precursor cells (EPCs) derived from neural crest cells (NCCs) during the enteric nervous system (ENS) embryogenesis. DNMT3b de novo methyltransferase is associated with NCCs development and has been shown to be implicated in ENS formation as well as in HSCR. In this study we have aimed to elucidate the specific mechanism underlying the DNMT3b role in such processes. We have performed the knockdown of Dnmt3b expression (Dnmt3b-KD) in enteric precursor cells (EPCs) to clarify its role on these cells in vitro. Moreover, we have analyzed several signaling pathways to determine the mechanisms responsible for the effect caused by Dnmt3b-KD in EPCs. Our results seem to support that Dnmt3b-KD promotes an increase EPCs proliferation that may be mediated by P53 and P21 activity, since both proteins were observed to be down-regulated in our Dnmt3b-KD cultures. Moreover, we observed a down-regulation of P53 and P21 in HSCR patients. These results lead us to propose that DNMT3b could be involved in HSCR through P53 and P21 activity., This work was supported by the project “PI16/01422” funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “Investing in your future”) and by the project “CTS-7447” funded by Regional Ministry of Innovation, Science and Enterprise of the Autonomous Government of Andalucia. L V-B is supported by a fellowship associated whit the CTS-7447 project.
- Published
- 2017