Villalba-Benito, LeticiaLópez-López, DanielTorroglosa, AnaCasimiro-Soriguer, Carlos S.Luzón-Toro, BertaFernández, Raquel MaríaMoya-Jiménez, María JoséAntiñolo, GuillermoDopazo, JoaquínBorrego, Salud2022-11-232022-11-232021-03-09Villalba-Benito L, López-López D, Torroglosa A, Casimiro-Soriguer CS, Luzón-Toro B, Fernández RM, et al. Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system development. Clin Epigenetics. 2021 Mar 9;13(1):51http://hdl.handle.net/10668/4394Background 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.enAtribución 4.0 InternacionalAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Hirschsprung diseaseWhole genome bisulfte sequencingDNA methylationEnteric nervous system developmentEpigenetic regulationNeural crestCpG islandsGenomeEnfermedad de hirschsprungSecuenciación completa del genomaMetilación de ADNSistema nervioso entéricoEpigenómicaCresta neuralIslas de CpGGenomaMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control StudiesMedical Subject Headings::Persons::Persons::Age Groups::Child::Child, PreschoolMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Base Sequence::GC Rich Sequence::CpG IslandsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA MethylationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, GeneticMedical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics::EpigenomicsMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to DiseaseMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::GenomeMedical Subject Headings::Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Congenital Abnormalities::Digestive System Abnormalities::Hirschsprung DiseaseMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Persons::Persons::Age Groups::InfantMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Anatomy::Embryonic Structures::Neural CrestMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Signal TransductionMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Motivation::GoalsMedical Subject Headings::Anatomy::Nervous System::Peripheral Nervous System::Autonomic Nervous System::Enteric Nervous SystemMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell ProliferationMedical Subject Headings::Information Science::Information Science::Information Storage and Retrieval::Databases as Topic::Databases, Factual::Databases, Geneticresearch article33750457open access10.1186/s13148-021-01040-61868-7083PMC7942176