Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development
Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development
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DOI：
10.1016/j.ydbio.2019.08.002
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发表时间：
2019-11-15
影响因子：
2.7
通讯作者：
Eisen, Judith S.
中科院分区：
文献类型：
--
作者：
Ganz, Julia;Melancon, Ellie;Eisen, Judith S.
肠道发育是一个协调的过程，涉及来自所有三个胚层的祖细胞和发育细胞之间的信号传导。内胚层来源的肠上皮细胞的发育已被证明依赖于表观遗传修饰，但这是否也适用于其他胚层的肠道细胞类型仍不清楚。我们发现，DNA甲基化机制的组成部分，泛蛋白样蛋白含有PHD和环指结构域1（uhrf 1）的功能丧失，导致外胚层来源的肠神经元的数量减少和中胚层来源的肠平滑肌的严重破坏。遗传嵌合体显示，Uhrf 1在肠神经元前体中的细胞自主功能和在周围肠细胞中的细胞非自主功能，这与已知的促进彼此发育的这些细胞类型之间的信号相互作用一致。Uhrf 1在复制过程中招募DNA甲基转移酶Dnmt 1到未甲基化的DNA。Dnmt 1也在肠神经元和平滑肌祖细胞中表达。与野生型相比，DNMT 1突变体具有较少的肠神经元和破坏的肠平滑肌。因为醉1; uhrf 1双突变体具有与dnmt 1和uhrf 1单突变体相似的表型，在肠神经元和肠肌肉发育过程中，dnmt 1和uhrf 1必须共同起作用。这项工作表明，控制表观遗传修饰的基因对协调肠道发育很重要，首次证明这些基因影响ENS的发育，并将uhrf 1和dnmt 1作为潜在的新的先天性巨结肠候选基因。
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 drunt1;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.