Epigenetics in ENS development and Hirschsprung disease

Abstract

Hirschsprung disease (HSCR, OMIM 142623) is a neurocristopathy caused by a failure of the enteric nervous system (ENS) progenitors derived from neural crest cells (NCCs), to migrate, proliferate, differentiate or survive to and within the gastrointestinal tract, resulting in aganglionosis in the distal colon. The formation of the ENS is a complex process, which is regulated by a large range of molecules and signalling pathways involving both the NCCs and the intestinal environment. This tightly regulated process needs correct regulation of the expression of ENS specific genes. Alterations in the expression of these genes can have dramatic consequences. Several mechanisms that control the expression of genes have been described, such as DNA modification (epigenetic mechanisms), regulation of transcription (transcription factor, enhancers, repressors and silencers), post-transcriptional regulation (3'UTR and miRNAs) and regulation of translation. In this review, we focus on the epigenetic DNA modifications that have been described so far in the context of the ENS development. Moreover we describe the changes that are found in relation to the onset of HSCR.

Overexpression of DNMT3b target genes during Enteric Nervous System development contribute to the onset of Hirschsprung disease

“…There are growing evidences indicating that epigenetic mechanisms have an essential role for the proper ENS and NCCs development 8 . In this sense, the de novo methyltransferase DNMT3b has been associated with HSCR 7 and, therefore, we have focused in the identification of DNMT3b target genes to elucidate the pathways and genes which are regulated by this methyltranferase.…”

“…Epigenetic mechanisms are acquiring increasing evidence of playing a major role in the onset of HSCR 7, 8 . Different epigenetic mechanisms are known, such as DNA methylation by the DNA methyltransferases (DNMT1, DNMT3a and DNMT3b).…”

Effects of Antioxidant Supplements on the Survival and Differentiation of Stem Cells

“…Moreover, NO levels were linked to neural precursor cell (NPC) survival and cell fate determination [49], that is, elevated levels of NO suppress NSC proliferation and enhance differentiation of NPCs into astrocytes [50, 51]. Melatonin is a hormone synthesized in the pineal gland [52] with indirect antioxidant abilities through induction of antioxidant enzymes [53] and inhibiting NO production in glial cultures through p38 inhibition [54].…”

Epigenetic factors coordinate intestinal development

“…Interestingly, DNMT1 is dysregulated in one type of IBD, Crohn's disease (Jorgensen et al, 2018). DNA hypomethylation has also been implicated in ENS-mediated diseases, particularly HSCR and Waardenburg syndrome (Kim et al, 2011;Torroglosa et al, 2016;Torroglosa et al, 2014). Changes in maintenance of DNA methylation can change gene expression patterns and several HSCR loci including RET, EDNRB, and HSCR candidate genes, such as PAX6, have been shown to be affected by changes in DNA methylation in their promoters (Torroglosa et al, 2016).…”

“…DNA hypomethylation has also been implicated in ENS-mediated diseases, particularly HSCR and Waardenburg syndrome (Kim et al, 2011;Torroglosa et al, 2016;Torroglosa et al, 2014). Changes in maintenance of DNA methylation can change gene expression patterns and several HSCR loci including RET, EDNRB, and HSCR candidate genes, such as PAX6, have been shown to be affected by changes in DNA methylation in their promoters (Torroglosa et al, 2016). Epigenetic modulation of methylation is also linked to other intestinal diseases, for example intestinal cancers (Gays et al, 2017).…”