Kobayashi Hiroshi, Kikyo Nobuaki
Stem Cell Institute, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN.
Stem Cell Institute, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN.
Transl Res. 2015 Jan;165(1):18-27. doi: 10.1016/j.trsl.2014.03.004. Epub 2014 Mar 13.
The recent progress in pluripotent stem cell research has opened new avenues of disease modeling, drug screening, and transplantation of patient-specific tissues unimaginable until a decade ago. The central mechanism underlying pluripotency is epigenetic gene regulation; the majority of cell signaling pathways, both extracellular and cytoplasmic, alter, eventually, the epigenetic status of their target genes during the process of activating or suppressing the genes to acquire or maintain pluripotency. It has long been thought that the chromatin of pluripotent stem cells is open globally to enable the timely activation of essentially all genes in the genome during differentiation into multiple lineages. The current article reviews descriptive observations and the epigenetic machinery relevant to what is supposed to be globally open chromatin in pluripotent stem cells, including microscopic appearance, permissive gene transcription, chromatin remodeling complexes, histone modifications, DNA methylation, noncoding RNAs, dynamic movement of chromatin proteins, nucleosome accessibility and positioning, and long-range chromosomal interactions. Detailed analyses of each element, however, have revealed that the globally open chromatin hypothesis is not necessarily supported by some of the critical experimental evidence, such as genomewide nucleosome accessibility and nucleosome positioning. Greater understanding of epigenetic gene regulation is expected to determine the true nature of the so-called globally open chromatin in pluripotent stem cells.
多能干细胞研究的最新进展开辟了疾病建模、药物筛选以及患者特异性组织移植的新途径，而就在十年前这些都是无法想象的。多能性的核心机制是表观遗传基因调控；大多数细胞信号通路，包括细胞外和细胞质的信号通路，最终都会在激活或抑制基因以获得或维持多能性的过程中改变其靶基因的表观遗传状态。长期以来，人们一直认为多能干细胞的染色质在全局上是开放的，以便在分化为多个谱系的过程中及时激活基因组中的几乎所有基因。本文综述了与多能干细胞中所谓全局开放染色质相关的描述性观察结果和表观遗传机制，包括微观外观、允许的基因转录、染色质重塑复合物、组蛋白修饰、DNA甲基化、非编码RNA、染色质蛋白的动态运动、核小体可及性和定位以及长程染色体相互作用。然而，对每个元素的详细分析表明，一些关键实验证据，如全基因组核小体可及性和核小体定位，并不能必然支持全局开放染色质假说。对表观遗传基因调控更深入的理解有望确定多能干细胞中所谓全局开放染色质的真实性质。
