RT Journal Article
SR Electronic
T1 Epigenetic factors coordinate intestinal development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 399410
DO 10.1101/399410
A1 Julia Ganz
A1 Ellie Melancon
A1 Catherine Wilson
A1 Angel Amores
A1 Peter Batzel
A1 Marie Strader
A1 Ingo Braasch
A1 Parham Diba
A1 Julie A. Kuhlman
A1 John H. Postlethwait
A1 Judith S. Eisen
YR 2018
UL http://biorxiv.org/content/early/2018/08/23/399410.abstract
AB Intestinal 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.Summary This work provides evidence that DNA methylation factors are important in all cell types that contribute to development of a functional intestine.