PUBLICATION

Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development

Authors
Ganz, J., Melancon, E., Wilson, C., Amores, A., Batzel, P., Strader, M., Braasch, I., Diba, P., Kuhlman, J.A., Postlethwait, J.H., Eisen, J.S.
ID
ZDB-PUB-200515-13
Date
2019
Source
Developmental Biology   455: 473-484 (Journal)
Registered Authors
Amores, Angel, Braasch, Ingo, Eisen, Judith S., Ganz, Julia, Kuhlman, Julie, Postlethwait, John H., Wilson, Catherine
Keywords
DNA methylation, Enteric nervous system, Hirschsprung disease, Intestinal development, Intestinal epithelium, Intestinal smooth muscle
MeSH Terms
  • Male
  • Epigenesis, Genetic*
  • Chimera
  • DNA (Cytosine-5-)-Methyltransferase 1/genetics
  • DNA (Cytosine-5-)-Methyltransferase 1/physiology*
  • Intestines/cytology
  • Intestines/embryology*
  • Intestines/innervation
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology*
  • Embryonic Stem Cells/metabolism
  • Enteric Nervous System/embryology*
  • Animals
  • Muscle, Smooth/embryology
  • Trans-Activators/genetics
  • Trans-Activators/physiology*
  • Mutation
  • Female
  • Gene Expression Regulation, Developmental
  • Neurons
  • Zebrafish
(all 21)
PubMed
31394080 Full text @ Dev. Biol.
Abstract
Intestinal tract development is a coordinated process involving signaling among the progenitors and developing cells from all three germ layers. Development of endoderm-derived intestinal epithelium has been shown to depend on epigenetic modifications, but whether that is also the case for intestinal tract cell types from other germ layers 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 numbers of ectoderm-derived enteric neurons and severe disruption of mesoderm-derived intestinal smooth muscle. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron precursors and cell-non-autonomously in surrounding intestinal cells, consistent with what is known about signaling interactions between these cell types that promote one another's development. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neurons and smooth muscle progenitors. dnmt1 mutants have fewer enteric neurons and disrupted intestinal smooth muscle compared to wildtypes. 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 to coordinate intestinal tract development, provides the first demonstration that these genes influence development of the ENS, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates.
Genes / Markers
Figures
Figure Gallery (9 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b1115
    Point Mutation
    hi272TgTransgenic Insertion
    s904
      Point Mutation
      w37TgTransgenic Insertion
        1 - 4 of 4
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        No data available
        Fish
        Antibodies
        Name Type Antigen Genes Isotypes Host Organism
        Ab1-desmpolyclonalRabbit
        Ab1-dnmt1polyclonalIgGRabbit
        Ab1-elavlmonoclonalIgG2bMouse
        Ab1-myh11polyclonalIgGRabbit
        Ab1-nospolyclonal
          IgGRabbit
          1 - 5 of 5
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          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          1 - 1 of 1
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          Mapping
          No data available