Epigenetic factors coordinate intestinal development

Abstract

This work provides evidence that DNA methylation factors are important in all cell types that contribute to development of a functional intestine. AbstractIntestinal epithelium development depends on epigenetic modifications, but whether that is also the case for other intestinal tract cell types remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced enteric neuron number, changes in neuronal morphology, and severe intestinal smooth muscle disruption. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron progenitors and cell-non-autonomously in surrounding intestinal cells. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neuron and smooth muscle progenitors. dnmt1 mutants show a strong reduction in enteric neuron number and disrupted intestinal smooth muscle. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important in coordinating intestinal tract development, provides the first demonstration that these genes are important in ENS development, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates. We thank Doug Turnbull and the University of Oregon Genomics and Cell Characterization Core Facility for their expertise in Illumina sequencing and bioinformatics, Poh Kheng Loi for histology, Adam Christensen, John Dowd and the UO Zebrafish Facility staff for assistance with zebrafish husbandry.

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“…This enables investigation of the localization and cross-species dynamics of fluorescently labelled bacterial species as well as GI function such as motility and barrier function. Additionally, the gut is simply cut open, making it possible to remove the microbiota for 16S sequencing 85,86,87 . Zebrafish have a considerable advantage over mammalian models when it comes to GI research because of their external fertilisation, rapid development also early transparency, which make investigating GI function in vivo much simpler.…”

Development, Diversity, and Neurogenic Capacity of Enteric Glia

“…Specific DNMTs, such as DNMT3b, and methyl binding proteins, such as MeCP2 have been identified to play a role in neural crest and ENS development (Zhou et al, 2013;Villalba-Benito et al, 2017). Knocking down dnmt1 and uhrf1 (another DNA binding protein which recruits histone deacetylases) in zebrafish leads to reduced ENCC colonisation of the gut (Ganz et al, 2019). In addition, the methylation of a promoter area has been shown to influence expression of key ENS development genes, such as Ret (Munnes et al, 1998) and Ednrb (Tang et al, 2013).…”