Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development

Background: Hirschsprung disease (HSCR, OMIM 142623) is a rare congenital disorder that results from a failure to fully colonize the gut by enteric precursor cells (EPCs) derived from the neural crest. Such incomplete gut colonization is due to alterations in EPCs proliferation, survival, migration...

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Autores: Villalba-Benito, Leticia, López-López, Daniel, Torroglosa, Ana, Casimiro-Soriguer, Carlos S., Luzón-Toro, Berta, Fernández, Raquel María, Moya-Jiménez, María José, Antiñolo Gil, Guillermo, Dopazo, Joaquín, Borrego, Salud
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/137598
Acceso en línea:https://hdl.handle.net/11441/137598
https://doi.org/10.1186/s13148-021-01040-6
Access Level:acceso abierto
Palabra clave:Hirschsprung disease
Whole genome bisulfite sequencing
DNA methylation
Enteric nervous system development
Epigenetic regulation
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spelling Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system developmentVillalba-Benito, LeticiaLópez-López, DanielTorroglosa, AnaCasimiro-Soriguer, Carlos S.Luzón-Toro, BertaFernández, Raquel MaríaMoya-Jiménez, María JoséAntiñolo Gil, GuillermoDopazo, JoaquínBorrego, SaludHirschsprung diseaseWhole genome bisulfite sequencingDNA methylationEnteric nervous system developmentEpigenetic regulationBackground: Hirschsprung disease (HSCR, OMIM 142623) is a rare congenital disorder that results from a failure to fully colonize the gut by enteric precursor cells (EPCs) derived from the neural crest. Such incomplete gut colonization is due to alterations in EPCs proliferation, survival, migration and/or differentiation during enteric nervous system (ENS) development. This complex process is regulated by a network of signaling pathways that is orchestrated by genetic and epigenetic factors, and therefore alterations at these levels can lead to the onset of neurocristopathies such as HSCR. The goal of this study is to broaden our knowledge of the role of epigenetic mechanisms in the disease context, specifically in DNA methylation. Therefore, with this aim, a Whole-Genome Bisulfite Sequencing assay has been performed using EPCs from HSCR patients and human controls. Results: This is the first study to present a whole genome DNA methylation profile in HSCR and reveal a decrease of global DNA methylation in CpG context in HSCR patients compared with controls, which correlates with a greater hypomethylation of the differentially methylated regions (DMRs) identified. These results agree with the de novo Methyltransferase 3b downregulation in EPCs from HSCR patients compared to controls, and with the decrease in the global DNA methylation level previously described by our group. Through the comparative analysis of DMRs between HSCR patients and controls, a set of new genes has been identified as potential susceptibility genes for HSCR at an epigenetic level. Moreover, previous differentially methylated genes related to HSCR have been found, which validates our approach. Conclusions: This study highlights the relevance of an adequate methylation pattern for a proper ENS development. This is a research area that provides a novel approach to deepen our understanding of the etiopathogenesis of HSCR.Regional Ministry of Health and Family of the Regional Government of Andalusia, (PEER-0470–2019). L.V.-B.The Regional Ministry of Innovation, Science and Enterprise of the Regional Government of Andalusia, (CTS-7447)BMCCirugía2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/137598https://doi.org/10.1186/s13148-021-01040-6reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésClinical Epigenetics, 13 (1).PI16/0142, PI19/01550PEER-0470–2019). L.V.-B.CTS-7447https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01040-6#Sec1info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1375982026-06-17T12:51:07Z
dc.title.none.fl_str_mv Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development
title Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development
spellingShingle Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development
Villalba-Benito, Leticia
Hirschsprung disease
Whole genome bisulfite sequencing
DNA methylation
Enteric nervous system development
Epigenetic regulation
title_short Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development
title_full Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development
title_fullStr Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development
title_full_unstemmed Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development
title_sort Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development
dc.creator.none.fl_str_mv Villalba-Benito, Leticia
López-López, Daniel
Torroglosa, Ana
Casimiro-Soriguer, Carlos S.
Luzón-Toro, Berta
Fernández, Raquel María
Moya-Jiménez, María José
Antiñolo Gil, Guillermo
Dopazo, Joaquín
Borrego, Salud
author Villalba-Benito, Leticia
author_facet Villalba-Benito, Leticia
López-López, Daniel
Torroglosa, Ana
Casimiro-Soriguer, Carlos S.
Luzón-Toro, Berta
Fernández, Raquel María
Moya-Jiménez, María José
Antiñolo Gil, Guillermo
Dopazo, Joaquín
Borrego, Salud
author_role author
author2 López-López, Daniel
Torroglosa, Ana
Casimiro-Soriguer, Carlos S.
Luzón-Toro, Berta
Fernández, Raquel María
Moya-Jiménez, María José
Antiñolo Gil, Guillermo
Dopazo, Joaquín
Borrego, Salud
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Cirugía
dc.subject.none.fl_str_mv Hirschsprung disease
Whole genome bisulfite sequencing
DNA methylation
Enteric nervous system development
Epigenetic regulation
topic Hirschsprung disease
Whole genome bisulfite sequencing
DNA methylation
Enteric nervous system development
Epigenetic regulation
description Background: Hirschsprung disease (HSCR, OMIM 142623) is a rare congenital disorder that results from a failure to fully colonize the gut by enteric precursor cells (EPCs) derived from the neural crest. Such incomplete gut colonization is due to alterations in EPCs proliferation, survival, migration and/or differentiation during enteric nervous system (ENS) development. This complex process is regulated by a network of signaling pathways that is orchestrated by genetic and epigenetic factors, and therefore alterations at these levels can lead to the onset of neurocristopathies such as HSCR. The goal of this study is to broaden our knowledge of the role of epigenetic mechanisms in the disease context, specifically in DNA methylation. Therefore, with this aim, a Whole-Genome Bisulfite Sequencing assay has been performed using EPCs from HSCR patients and human controls. Results: This is the first study to present a whole genome DNA methylation profile in HSCR and reveal a decrease of global DNA methylation in CpG context in HSCR patients compared with controls, which correlates with a greater hypomethylation of the differentially methylated regions (DMRs) identified. These results agree with the de novo Methyltransferase 3b downregulation in EPCs from HSCR patients compared to controls, and with the decrease in the global DNA methylation level previously described by our group. Through the comparative analysis of DMRs between HSCR patients and controls, a set of new genes has been identified as potential susceptibility genes for HSCR at an epigenetic level. Moreover, previous differentially methylated genes related to HSCR have been found, which validates our approach. Conclusions: This study highlights the relevance of an adequate methylation pattern for a proper ENS development. This is a research area that provides a novel approach to deepen our understanding of the etiopathogenesis of HSCR.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/137598
https://doi.org/10.1186/s13148-021-01040-6
url https://hdl.handle.net/11441/137598
https://doi.org/10.1186/s13148-021-01040-6
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Clinical Epigenetics, 13 (1).
PI16/0142, PI19/01550
PEER-0470–2019). L.V.-B.
CTS-7447
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01040-6#Sec1
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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