<i>Dnmt3b</i> knock-down in enteric precursors reveals a possible mechanism by which this <i>de novo</i> methyltransferase is involved in the enteric nervous system development and the onset of Hirschsprung disease

Torroglosa, Ana; Villalba‐Benito, Leticia; Fernández, Raquel M.; Moya-Jiménez, María José; Antiñolo, Guillermo; Borrego, Salud

doi:10.18632/oncotarget.22473

Cited by 6 publications

(6 citation statements)

References 39 publications

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“…The onset of the intestinal Hirschsprung disease was associated with the overexpression of recognized DNMT3B target genes in enteric nervous system development ( Torroglosa et al, 2017 ; Villalba-Benito et al, 2017 ). Moreover, a promoter polymorphism (-579G > T) was associated with idiopathic thrombocytopenic purpura ( Zhao et al, 2009 ) and with a higher risk of thymomas in patients with myasthenia gravis ( Coppede et al, 2013 ).…”

Section: Alteration Of Dnmt3b Function In Human Diseasementioning

confidence: 99%

DNMT3B Functions: Novel Insights From Human Disease

Gagliardi

Strazzullo

Matarazzo

2018

Front. Cell Dev. Biol.

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DNA methylation plays important roles in gene expression regulation and chromatin structure. Its proper establishment and maintenance are essential for mammalian development and cellular differentiation. DNMT3B is the major de novo DNA methyltransferase expressed and active during the early stage of embryonic development, including implantation. In addition to its well-known role to methylate centromeric, pericentromeric, and subtelomeric repeats, recent observations suggest that DNMT3B acts as the main enzyme methylating intragenic regions of active genes. Although largely studied, much remains unknown regarding how these specific patterns of de novo CpG methylation are established in mammalian cells, and which are the rules governing DNMT3B recruitment and activity. Latest evidence indicates that DNMT3B recruitment is regulated by numerous mechanisms including chromatin modifications, transcription levels, non-coding RNAs, and the presence of DNA-binding factors. DNA methylation abnormalities are a common mark of human diseases involving chromosomal and genomic instabilities, such as inherited disease and cancer. The autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies syndrome, type I (ICF-1), is associated to hypomorphic mutations in DNMT3B gene, while its altered expression has been correlated with the development of tumors. In both cases, this implies that abnormal DNA hypomethylation and hypermethylation patterns affect gene expression and genomic architecture contributing to the pathological states. We will provide an overview of the most recent research aimed at deciphering the molecular mechanisms by which DNMT3B abnormalities are associated with the onset and progression of these pathologies.

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Section: Alteration Of Dnmt3b Function In Human Diseasementioning

confidence: 99%

DNMT3B Functions: Novel Insights From Human Disease

Gagliardi

Strazzullo

Matarazzo

2018

Front. Cell Dev. Biol.

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“…In addition, the synergistic effect of mutations in both DNMT3B and other HSCR–related genes on the severity of the phenotype in HSCR patients has been reported [24]. Such alterations resulted in an altered gene expression pattern [25] and an arrest of cell cycle of the EPCs through P53-P21 activity [26]. Therefore, all this evidence suggests the involvement of DNMT3B as a susceptibility gene for HSCR and demonstrates the crucial role of DNA methylation in ENS development and in the onset of HSCR.…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetic Mechanisms in Hirschsprung Disease

Torroglosa

Villalba‐Benito

Lasa

et al. 2019

IJMS

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Hirschsprung disease (HSCR, OMIM 142623) is due to a failure of enteric precursor cells derived from neural crest (EPCs) to proliferate, migrate, survive or differentiate during Enteric Nervous System (ENS) formation. This is a complex process which requires a strict regulation that results in an ENS specific gene expression pattern. Alterations at this level lead to the onset of neurocristopathies such as HSCR. Gene expression is regulated by different mechanisms, such as DNA modifications (at the epigenetic level), transcriptional mechanisms (transcription factors, silencers, enhancers and repressors), postranscriptional mechanisms (3′UTR and ncRNA) and regulation of translation. All these mechanisms are finally implicated in cell signaling to determine the migration, proliferation, differentiation and survival processes for correct ENS development. In this review, we have performed an overview on the role of epigenetic mechanisms at transcriptional and posttranscriptional levels on these cellular events in neural crest cells (NCCs), ENS development, as well as in HSCR.

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“…It has been described that the EPCs contained in the NLBs can be transplanted into the aganglionic intestine to restore their contractile properties [21,22]. In addition, in previous studies we validated EPC cultures for the study of the ENS and HSCR through different methodological approaches [23,24]. Therefore, the use of human EPCs is a "more physiological" tool than cell lines and a better system than gut tissue to study the regulatory mechanisms and implicated molecules during embryonic ENS development.…”

Section: Introductionmentioning

confidence: 97%

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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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

Cited by 6 publications

References 39 publications

DNMT3B Functions: Novel Insights From Human Disease

DNMT3B Functions: Novel Insights From Human Disease

Epigenetic Mechanisms in Hirschsprung Disease

Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease

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