Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells.
Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells.
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诱导多能干细胞（iPSC）已经通过在体细胞中强制表达限定的转录因子组而产生。iPSC在分子和功能上是否等同于胚泡来源的胚胎干细胞（ESCs）仍然存在争议。通过比较遗传上相同的小鼠ESC和iPSC，我们在这里表明，这些细胞类型的总体mRNA和miRNA表达模式是不可区分的，除了染色体12 qF 1上编码的一些转录本和miRNA。具体地，Dlk 1-Dio 3簇中的母系表达的印迹基因包括Gtl 2、Rian和Mirg以及在该区域内编码的大量miRNA在大多数iPSC克隆中异常沉默，而不管它们的细胞类型来源。与Dlk 1-Dio 3基因簇的发育作用一致，具有阻遏的Gt 12的iPSC克隆对嵌合体的贡献很小，并且不能支持完全iPSC衍生的动物（“全iPSC小鼠”）的发育。相比之下，具有这些基因的正常表达水平的iPSC克隆有助于高等级嵌合体并产生可行的全iPSC小鼠。重要的是，用组蛋白去乙酰化酶抑制剂治疗沉默Dlk 1-Dio 3并且未能产生全iPSC动物的iPSC克隆重新激活了该基因座，并挽救了其支持完全iPSC衍生小鼠的足月发育的能力。因此，单个印记基因簇的表达状态将大多数鼠iPSC与ESC区分开，并且允许前瞻性地鉴定具有ESC的全部发育潜力的iPSC克隆。
Induced pluripotent stem cells (iPSCs) have been generated by enforced expression of defined sets of transcription factors in somatic cells. It remains controversial whether iPSCs are molecularly and functionally equivalent to blastocyst-derived embryonic stem cells (ESCs). By comparing genetically identical mouse ESCs and iPSCs, we show here that the overall mRNA and miRNA expression patterns of these cell types are indistinguishable with the exception of a few transcripts and miRNAs encoded on chromosome 12qF1. Specifically, maternally expressed imprinted genes in the Dlk1-Dio3 cluster including Gtl2, Rian and Mirg as well as a larger number of miRNAs encoded within this region were aberrantly silenced in the majority of iPSC clones, irrespective of their cell type of origin. Consistent with a developmental role of the Dlk1-Dio3 gene cluster, iPSC clones with repressed Gtl2 contributed poorly to chimeras and failed to support the development of entirely iPSC-derived animals (“all-iPSC mice”). In contrast, iPSC clones with normal expression levels of these genes contributed to high-grade chimeras and generated viable all-iPSC mice. Importantly, treatment of an iPSC clone that had silenced Dlk1-Dio3 and failed to give rise to all-iPSC animals with a histone deacetylase inhibitor reactivated the locus and rescued its ability to support full-term development of exclusively iPSC-derived mice. Thus, the expression state of a single imprinted gene cluster distinguishes most murine iPSCs from ESCs and allows for the prospective identification of iPSC clones that have the full development potential of ESCs.
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