DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease.
DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease.
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DOI：
10.1038/s41419-018-0495-z
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Ro S
中科院分区：
文献类型：
--
作者：
Jorgensen BG;Berent RM;Ha SE;Horiguchi K;Sasse KC;Becker LS;Ro S
DNA甲基化是调控基因表达的关键表观遗传修饰。基因组DNA低甲基化在许多胃肠道疾病中都很常见。GI平滑肌细胞（GI- smcs）基因表达失调可导致运动障碍。然而，基因组DNA低甲基化在GI-SMCs中的后果仍然难以捉摸。利用Cre-lox小鼠模型，我们产生了smc限制性DNA甲基转移酶1 （Dnmt1）敲除（KO）小鼠，并分析了Dnmt1缺乏的影响。Dnmt1-KO幼崽出生时比野生型幼崽小，胃肠道缩短，由于肠道肌肉膜的丧失而失去蠕动，导致肠道大规模扩张，并在出生后21天左右死亡。在平滑肌组织中，显著的CpG低甲基化发生在整个基因组的启动子、内含子和外显子上。此外，分化的SMC标记物（Srf, Myh11, miR-133, miR-143/145）的明显缺失，促凋亡标记物（Nr4a1, Gadd45g）的增加，细胞连通性的丧失以及SMC内包被囊泡的积累。有趣的是，我们观察到Dnmt1-KO小鼠和患病人类胃肠道组织中参与DNA甲基化的酶的异常表达模式一致。这些数据表明，胚胎SMC中的DNA低甲基化，通过先天性Dnmt1缺陷，导致基因表达大量失调，并对GI-SMC致命。这些结果表明Dnmt1在SMC的胚胎初级发育过程中具有必要的作用，并且在人类胃肠道病变组织中发现了一致的模式。
DNA methylation is a key epigenetic modification that can regulate gene expression. Genomic DNA hypomethylation is commonly found in many gastrointestinal (GI) diseases. Dysregulated gene expression in GI smooth muscle cells (GI-SMCs) can lead to motility disorders. However, the consequences of genomic DNA hypomethylation within GI-SMCs are still elusive. Utilizing a Cre-lox murine model, we have generated SMC-restricted DNA methyltransferase 1 (Dnmt1) knockout (KO) mice and analyzed the effects of Dnmt1 deficiency. Dnmt1-KO pups are born smaller than their wild-type littermates, have shortened GI tracts, and lose peristaltic movement due to loss of the tunica muscularis in their intestine, causing massive intestinal dilation, and death around postnatal day 21. Within smooth muscle tissue, significant CpG hypomethylation occurs across the genome at promoters, introns, and exons. Additionally, there is a marked loss of differentiated SMC markers (Srf, Myh11, miR-133, miR-143/145), an increase in pro-apoptotic markers (Nr4a1, Gadd45g), loss of cellular connectivity, and an accumulation of coated vesicles within SMC. Interestingly, we observed consistent abnormal expression patterns of enzymes involved in DNA methylation between both Dnmt1-KO mice and diseased human GI tissue. These data demonstrate that DNA hypomethylation in embryonic SMC, via congenital Dnmt1 deficiency, contributes to massive dysregulation of gene expression and is lethal to GI-SMC. These results suggest that Dnmt1 has a necessary role in the embryonic, primary development process of SMC with consistent patterns being found in human GI diseased tissue.
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影响因子：
7.7
作者：
Elliott EN;Sheaffer KL;Kaestner KH
通讯作者：
Kaestner KH
影响因子：
--
作者：
Jin, Bilian;Robertson, Keith D.
通讯作者：
Robertson, Keith D.
影响因子：
64.8
作者：
Cordes KR;Sheehy NT;White MP;Berry EC;Morton SU;Muth AN;Lee TH;Miano JM;Ivey KN;Srivastava D
通讯作者：
Srivastava D
影响因子：
12.3
作者：
Li Z;Dai H;Martos SN;Xu B;Gao Y;Li T;Zhu G;Schones DE;Wang Z
通讯作者：
Wang Z
影响因子：
7
作者：
Hinoue, Toshinori;Weisenberger, Daniel J.;Laird, Peter W.
通讯作者：
Laird, Peter W.