Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration.
Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration.
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DOI：
10.1016/j.ydbio.2009.07.017
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发表时间：
2009-10-01
影响因子：
2.7
通讯作者：
Stainier, Didier Y. R.
中科院分区：
文献类型：
--
作者：
Anderson, Ryan M.;Bosch, Justin A.;Goll, Mary G.;Hesselson, Daniel;Dong, P. Duc Si;Shin, Donghun;Chi, Neil C.;Shin, Chong Hyun;Schlegel, Amnon;Halpern, Marnie;Stainier, Didier Y. R.
调节基因表达的发育机制和细胞命运的稳定获得指导器官发生期间的细胞分化。此外，这种机制很可能被用来修复或再生受损器官。DNA甲基转移酶（DNA methyltransferases，Dnmts）是表观遗传调控的关键酶，与组蛋白甲基化和乙酰化共同调控基因表达，维持基因组完整性和染色体结构。我们进行了两个内胚层器官发育调节基因的正向筛选。在第一个实验中，我们筛选了发育中消化器官的形态学改变，而在第二个实验中，我们筛选了胰腺和肝脏中缺乏终末分化细胞类型。从这些屏幕上，我们确定了两个斑马鱼dnmt 1的突变等位基因。这两种病变预测消除dnmt 1功能;一个是错义突变的催化结构域和其他是无义突变，消除催化结构域。在斑马鱼dnmt 1突变体中，胰腺和肝脏正常形成，但在受精后84小时（hpf）开始退化。腺泡细胞几乎废除通过凋亡100 hpf，虽然既没有DNA复制，也没有进入有丝分裂停止在检测Dnmt 1的情况下。然而，内分泌细胞和导管在很大程度上幸免。令人惊讶的是，dnmt 1突变体和dnmt 1吗啉代注射的幼虫在胰腺β细胞消融的诱导模型中显示出胰腺β细胞再生的能力增加。因此，我们的数据表明，Dnmt 1是胰管或内分泌细胞形成的关键，但不是腺泡细胞存活的关键。此外，Dnmt 1可能影响胰腺β细胞祖细胞的分化或细胞向胰腺β细胞命运的重编程。
Developmental mechanisms regulating gene expression and the stable acquisition of cell fate direct cytodifferentiation during organogenesis. Moreover, it is likely that such mechanisms could be exploited to repair or regenerate damaged organs. DNA methyltransferases (Dnmts) are enzymes critical for epigenetic regulation, and are used in concert with histone methylation and acetylation to regulate gene expression and maintain genomic integrity and chromosome structure. We carried out two forward genetic screens for regulators of endodermal organ development. In the first, we screened for altered morphology of developing digestive organs, while in the second we screed for the lack of terminally differentiated cell types in the pancreas and liver. From these screens, we identified two mutant alleles of zebrafish dnmt1. Both lesions are predicted to eliminate dnmt1 function; one is a missense mutation in the catalytic domain and the other is a nonsense mutation that eliminates the catalytic domain. In zebrafish dnmt1 mutants, the pancreas and liver form normally, but begin to degenerate after 84 hours post fertilization (hpf). Acinar cells are nearly abolished through apoptosis by 100 hpf, though neither DNA replication, nor entry into mitosis are halted in the absence of detectable Dnmt1. However, endocrine cells and ducts are largely spared. Surprisingly, dnmt1 mutants and dnmt1 morpholino-injected larvae show increased capacity for pancreatic beta cell regeneration in an inducible model of pancreatic beta cell ablation. Thus, our data suggest that Dnmt1 is dispensable for pancreatic duct or endocrine cell formation, but not for acinar cell survival. In addition, Dnmt1 may influence the differentiation of pancreatic beta cell progenitors or the reprogramming of cells toward the pancreatic beta cell fate.
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影响因子：
9.8
作者：
Brennand K;Huangfu D;Melton D
通讯作者：
Melton D
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作者：
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作者：
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