Research Papers:

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

Ana Torroglosa, Leticia Villalba-Benito, Raquel María Fernández, María José Moya-Jiménez, Guillermo Antiñolo and Salud Borrego _

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Oncotarget. 2017; 8:106443-106453. https://doi.org/10.18632/oncotarget.22473

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Ana Torroglosa1,2,*, Leticia Villalba-Benito1,2,*, Raquel María Fernández1,2, María José Moya-Jiménez3, Guillermo Antiñolo1,2 and Salud Borrego1,2

1Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío, CSIC, University of Seville, Seville 41013, Spain

2Center for Biomedical Network Research on Rare Diseases, Seville 41013, Spain

3Department of Pediatric Surgery, University Hospital Virgen del Rocío, Seville 41013, Spain

*These authors contributed equally to this work

Correspondence to:

Salud Borrego, email: [email protected]

Keywords: Hirschsprung disease; DNMT3b; ENS development; P53; P21

Received: July 27, 2017     Accepted: October 27, 2017     Published: November 16, 2017


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.

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