Epigenetic Mechanisms in Hirschsprung Disease

Torroglosa, Ana; Villalba‐Benito, Leticia; Lasa, Berta; Fernández, Raquel M.; Antiñolo, Guillermo; Borrego, Salud

doi:10.3390/ijms20133123

Cited by 23 publications

(16 citation statements)

References 123 publications

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“…Another study has shown that loss of genes coding for the ubiquitin-like protein containing PHD and RING finger domains 1 (Uhrf1), and DNA methyltransferase 1 (Dnmt1) reduced the number of enteric neurons and disrupted intestinal smooth muscle in zebrafish (Ganz et al, 2019 ). Although epigenetic mechanisms, including hypomethylation, have been suggested as a disease mechanism for HSCR [reviewed in Torroglosa et al ( 2019 )], this was the first report of a genetic animal model of aberrant methylation, that showed an effect on ENS development in vivo (Ganz et al, 2019 ). It would be of high interest to investigate the downstream transcriptional consequences of hypomethylation in enteric neurons, to further expand our understanding on HSCR pathogenicity.…”

Section: Genetic Modifications In Zebrafish To Study Ens Developmentmentioning

confidence: 99%

Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease

Kuil¹,

Chauhan²,

Cheng³

et al. 2021

Front. Cell Dev. Biol.

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The Enteric Nervous System (ENS) is a large network of enteric neurons and glia that regulates various processes in the gastrointestinal tract including motility, local blood flow, mucosal transport and secretion. The ENS is derived from stem cells coming from the neural crest that migrate into and along the primitive gut. Defects in ENS establishment cause enteric neuropathies, including Hirschsprung disease (HSCR), which is characterized by an absence of enteric neural crest cells in the distal part of the colon. In this review, we discuss the use of zebrafish as a model organism to study the development of the ENS. The accessibility of the rapidly developing gut in zebrafish embryos and larvae, enables in vivo visualization of ENS development, peristalsis and gut transit. These properties make the zebrafish a highly suitable model to bring new insights into ENS development, as well as in HSCR pathogenesis. Zebrafish have already proven fruitful in studying ENS functionality and in the validation of novel HSCR risk genes. With the rapid advancements in gene editing techniques and their unique properties, research using zebrafish as a disease model, will further increase our understanding on the genetics underlying HSCR, as well as possible treatment options for this disease.

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Section: Genetic Modifications In Zebrafish To Study Ens Developmentmentioning

confidence: 99%

Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease

Kuil¹,

Chauhan²,

Cheng³

et al. 2021

Front. Cell Dev. Biol.

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“…A growing amount of research has shown that noncoding RNAs are potential markers of disease risk and prognosis in various diseases. 2 , 8 , 36 , 37 , 45 – 47 A decrease in miR-141 can target downstream genes, increasing the expression of integrin-associated protein and cullin 3, which play important roles in inhibiting cell migration and proliferation during the pathogenesis of HSCR. 48 The miRNA miRNA-206 has also been shown to be downregulated and targets fibronectin 1 (FN1), serum deprivation response, and paired box 3 in Chinese patients with HSCR.…”

Section: Discussionmentioning

confidence: 99%

“…A growing number of genes and genetic pathways that play a critical functional role in neural crest cell development have been confirmed to be related to the pathogenesis of HSCR. 2 , 7 – 9 . However, mutations in genes account for only approximately half of the known mutations found in patients with HSCR.…”

Section: Introductionmentioning

confidence: 99%

Association between miR-492 rs2289030 G>C and susceptibility to Hirschsprung disease in southern Chinese children

et al. 2020

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Objective Hirschsprung disease (HSCR) originates from disruption of normal neural crest cell migration, differentiation, and proliferation during the fifth to eighth weeks of gestation. This results in the absence of intestinal ganglion cells in the distal intestinal tract. However, genetic variations affecting embryonic development of intestinal ganglion cells are unclear. Therefore, this study aimed to investigated the potential value of miR-492 rs2289030 G>C as a marker of susceptibility to HSCR Methods In this case–control study in southern Chinese children, we collected samples from 1473 controls and 1470 patients with HSCR. TaqMan genotyping of miR-492 rs2289030 G>C was performed by real-time fluorescent quantitative polymerase chain reaction. Results Multivariate logistic regression analysis showed that there was no significant association between the presence of the miR-492 rs2289030 G>C polymorphism and susceptibility to HSCR by evaluating the values of pooled odds ratios and 95% confidence intervals. Similarly, among different HSCR subtypes, rs2289030 G>C was also not associated with HSCR in hierarchical analysis. Conclusions Our results suggest that the miR-492 rs2289030 G>C polymorphism is not associated with susceptibility to HSCR in southern Chinese children. These results need to be further confirmed by investigating a more diverse ethnic population of patients with HSCR.

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“…As a consequence, ENS formation requires an exhaustive control at those different levels, and alterations at any of them may result in the onset of HSCR. In this sense, the epigenetic mechanisms play an important role on the establishment of the specific gene expression patterns in many biological processes, constituting an emerging research area in the study of ENS development and specifically in HSCR [9].…”

Section: Introductionmentioning

confidence: 99%

“…These molecules have been widely related to different pathologies, especially in cancer, and in this case it is worth noting those that affect the nervous system, as is the case of the ENS that results in the appearance and progression of HSCR. These molecules have acquired an important role as biomarkers in this pathology, hence the interest in studying them [9,[17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease

Torroglosa

Villalba‐Benito

Fernández

et al. 2020

IJMS

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Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic mechanisms are gaining increasing relevance. In an effort to better understand the epigenetic basis of HSCR, we have performed an analysis for the identification of long non-coding RNAs (lncRNAs) by qRT-PCR in enteric precursor cells (EPCs) from controls and HSCR patients. We aimed to test the presence of a set lncRNAs among 84 lncRNAs in human EPCs, which were previously related with crucial cellular processes for ENS development, as well as to identify the possible differences between HSCR patients and controls. As a result, we have determined a set of lncRNAs with positive expression in human EPCs that were screened for mutations using the exome data from our cohort of HSCR patients to identify possible variants related to this pathology. Interestingly, we identified three lncRNAs with different levels of their transcripts (SOCS2-AS, MEG3 and NEAT1) between HSCR patients and controls. We propose such lncRNAs as possible regulatory elements implicated in the onset of HSCR as well as potential biomarkers of this pathology.

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Epigenetic Mechanisms in Hirschsprung Disease

Cited by 23 publications

References 123 publications

Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease

Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease

Association between miR-492 rs2289030 G>C and susceptibility to Hirschsprung disease in southern Chinese children

Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease

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