Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all–iPS cell mice from terminally differentiated B cells
Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all–iPS cell mice from terminally differentiated B cells
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DOI：
10.1038/ng0712-831b
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发表时间：
2012-06
期刊：
影响因子：
30.8
通讯作者：
M. Stadtfeld;E. Apostolou;F. Ferrari;Jiho Choi;R. Walsh;Taiping Chen;Steen K. T. Ooi;Sang Y. Kim
中科院分区：
文献类型：
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作者：
M. Stadtfeld;E. Apostolou;F. Ferrari;Jiho Choi;R. Walsh;Taiping Chen;Steen K. T. Ooi;Sang Y. Kim
诱导性多能干细胞（iPSC）的产生通常导致ImprintedDlk 1-Dio 3基因簇的异常表观遗传沉默，损害产生完全iPSC衍生的成年小鼠（“全iPSC小鼠”）的能力。在这里，我们表明，在抗坏血酸的存在下，重编程减弱超甲基化的Dlk 1-Dio 3，使染色质的配置，干扰结合的de novoDNA甲基转移酶Dnmt 3a。这种方法使我们能够从成熟的B细胞中产生全iPSC小鼠，到目前为止，这还不能支持完全iPSC衍生的出生后动物的发育。我们的数据表明，转录因子介导的重编程可以赋予一个定义，终末分化的细胞类型与胚胎干细胞的发育潜力相当。更一般地，这些发现表明细胞重编程期间的培养条件可以强烈影响所得iPSC的表观遗传和生物学特性。
The generation of induced pluripotent stem cells (iPSCs) often results in aberrant epigenetic silencing of the imprintedDlk1-Dio3gene cluster, compromising the ability to generate entirely iPSC-derived adult mice ('all-iPSC mice'). Here, we show that reprogramming in the presence of ascorbic acid attenuates hypermethylation ofDlk1-Dio3by enabling a chromatin configuration that interferes with binding of thede novoDNA methyltransferase Dnmt3a. This approach allowed us to generate all-iPSC mice from mature B cells, which have until now failed to support the development of exclusively iPSC-derived postnatal animals. Our data show that transcription factor–mediated reprogramming can endow a defined, terminally differentiated cell type with a developmental potential equivalent to that of embryonic stem cells. More generally, these findings indicate that culture conditions during cellular reprogramming can strongly influence the epigenetic and biological properties of the resultant iPSCs.