Naive Human Pluripotent Cells Feature a Methylation Landscape Devoid of Blastocyst or Germline Memory.
Naive Human Pluripotent Cells Feature a Methylation Landscape Devoid of Blastocyst or Germline Memory.
复制标题
DOI：
10.1016/j.stem.2016.01.019
复制
发表时间：
2016-03-03
期刊：
影响因子：
23.9
通讯作者：
Clark AT
中科院分区：
文献类型：
--
作者：
Pastor WA;Chen D;Liu W;Kim R;Sahakyan A;Lukianchikov A;Plath K;Jacobsen SE;Clark AT
人胚胎干细胞（hESC）通常表现出“引发的”多能性，类似于源自小鼠植入后外胚层的干细胞。这导致了对支持hESC自我更新的生长条件的研究，所述hESC类似于人类植入前胚胎中的低甲基化幼稚外胚层细胞。我们已经发现，将引发的hESC恢复到低甲基化的幼稚状态或在幼稚条件下衍生新的hESC系导致建立具有类似于人类植入前上胚层的转录程序的阶段特异性胚胎抗原4（SSEA 4）阴性hESC系。相比之下，我们发现体外幼稚hESC的甲基化组与体内人上胚层不同，在初级印记处DNA甲基化丧失，并且人卵母细胞甲基化状态的“记忆”丧失。这种无法恢复幼稚外胚层甲基化景观似乎是体外自我更新低甲基化幼稚hESC的一致特征。
Human embryonic stem cells (hESCs) typically exhibit “primed” pluripotency, analogous to stem cells derived from the mouse post-implantation epiblast. This has led to a search for growth conditions that support self-renewal of hESCs akin to hypomethylated naïve epiblast cells in human pre-implantation embryos. We have discovered that reverting primed hESCs to a hypomethylated naïve state or deriving a new hESC line under naïve conditions results in the establishment of Stage Specific Embryonic Antigen 4 (SSEA4) negative hESC lines with a transcriptional program resembling the human pre-implantation epiblast. In contrast, we discovered that the methylome of naïve hESCs in vitro is distinct from the human epiblast in vivo with loss of DNA methylation at primary imprints and a lost “memory” of the methylation state of the human oocyte. This failure to recover the naïve epiblast methylation landscape appears to be a consistent feature of self-renewing hypomethylated naïve hESCs in vitro.