Dnmt3a 和 Dnmt3b 的从头 DNA 甲基化对于体细胞重编程为多能状态是可有可无的。
De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state.
机构信息
The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
出版信息
Genes Dev. 2011 May 15;25(10):1035-40. doi: 10.1101/gad.2039011.
Abstract
Induced pluripotent stem cells (iPSCs) are generated from somatic cells by the transduction of defined transcription factors, and this process involves dynamic changes in DNA methylation. While the reprogramming of somatic cells is accompanied by demethylation of pluripotency genes, the functional importance of de novo DNA methylation has not been clarified. Here, using loss-of-function studies, we generated iPSCs from fibroblasts that were deficient in de novo DNA methylation mediated by Dnmt3a and Dnmt3b. These iPSCs reactivated pluripotency genes, underwent self-renewal, and showed restricted developmental potential that was rescued upon reintroduction of Dnmt3a and Dnmt3b. We conclude that de novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells.
摘要
诱导多能干细胞（iPSCs）是通过转导特定转录因子从体细胞产生的，这一过程涉及 DNA 甲基化的动态变化。虽然体细胞的重编程伴随着多能性基因的去甲基化，但新合成 DNA 甲基化的功能重要性尚未阐明。在这里，我们利用功能丧失研究，从缺乏 Dnmt3a 和 Dnmt3b 介导的新合成 DNA 甲基化的成纤维细胞中生成 iPSCs。这些 iPSCs 重新激活了多能性基因，经历了自我更新，并表现出受限的发育潜能，在重新引入 Dnmt3a 和 Dnmt3b 后得到挽救。我们得出结论，Dnmt3a 和 Dnmt3b 的新合成 DNA 甲基化对于体细胞的核重编程是可有可无的。
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本文引用的文献
1
Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET.原病毒在胚胎干细胞中的沉默需要组蛋白甲基转移酶 ESET。
Nature. 2010 Apr 8;464(7290):927-31. doi: 10.1038/nature08858. Epub 2010 Feb 17.
2
Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts.组织和肿瘤特异性 CpG 岛侧翼的差异甲基化可区分人诱导多能干细胞、胚胎干细胞和成纤维细胞。
Nat Genet. 2009 Dec;41(12):1350-3. doi: 10.1038/ng.471. Epub 2009 Nov 1.
3
Adult mice generated from induced pluripotent stem cells.由诱导多能干细胞产生的成年小鼠。
Nature. 2009 Sep 3;461(7260):91-4. doi: 10.1038/nature08310.
4
iPS cells produce viable mice through tetraploid complementation.诱导多能干细胞通过四倍体补偿产生存活的小鼠。
Nature. 2009 Sep 3;461(7260):86-90. doi: 10.1038/nature08267.
5
iPS cells can support full-term development of tetraploid blastocyst-complemented embryos.诱导多能干细胞可支持四倍体囊胚互补胚胎的足月发育。
Cell Stem Cell. 2009 Aug 7;5(2):135-8. doi: 10.1016/j.stem.2009.07.001. Epub 2009 Jul 23.
6
Metastable pluripotent states in NOD-mouse-derived ESCs.NOD小鼠来源的胚胎干细胞中的亚稳定多能状态。
Cell Stem Cell. 2009 Jun 5;4(6):513-24. doi: 10.1016/j.stem.2009.04.015. Epub 2009 May 7.
7
A fresh look at iPS cells.对诱导多能干细胞的全新审视。
Cell. 2009 Apr 3;137(1):13-7. doi: 10.1016/j.cell.2009.03.034.
8
Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming.靶向亚硫酸氢盐测序揭示了与核重编程相关的DNA甲基化变化。
Nat Biotechnol. 2009 Apr;27(4):353-60. doi: 10.1038/nbt.1530. Epub 2009 Mar 29.
9
Epigenetic reprogramming and induced pluripotency.表观遗传重编程与诱导多能性。
Development. 2009 Feb;136(4):509-23. doi: 10.1242/dev.020867.
10
Induced pluripotent stem cell generation using a single lentiviral stem cell cassette.利用单个慢病毒干细胞盒诱导多能干细胞的产生。
Stem Cells. 2009 Mar;27(3):543-9. doi: 10.1634/stemcells.2008-1075.
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