Abstract
Abstract
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.
Graphic abstract
Funder
Instituto de Salud Carlos III
Consejería de Salud, Junta de Andalucía
Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Developmental Biology,Genetics,Molecular Biology
Reference40 articles.
1. Chakravarti A, Lyonnet, S. In The Metabolic and Molecular Bases of Inherited Disease. In: Beaudet AR, Scriver, C. R., Sly, W., Valle, D., editor. 8th ed: McGraw-Hill; 2001.
2. Luzón-Toro B, Villalba-Benito L, Torroglosa A, Fernández RM, Antiñolo G, Borrego S. What is new about the genetic background of Hirschsprung disease? Clin Genet. 2020;97(1):114–24.
3. Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 2008;45(1):1–14.
4. Lindley RM, Hawcutt DB, Connell MG, Edgar DH, Kenny SE. Properties of secondary and tertiary human enteric nervous system neurospheres. J Pediatr Surg. 2009;44(6):1249–55 (discussion 55-6).
5. Rauch U, Hänsgen A, Hagl C, Holland-Cunz S, Schäfer KH. Isolation and cultivation of neuronal precursor cells from the developing human enteric nervous system as a tool for cell therapy in dysganglionosis. Int J Colorectal Dis. 2006;21(6):554–9.
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献