【latex版】水贴

One of the most prominent drugs improving reprogramming is the histone deacetylase 1 (HDAC1) inhibitor valproic acid (VPA; Huangfu et al., 2008). The inhibition of HDAC1 seems to lower the epigenetic barrier between the cell states and facilitates the transition from one state to the other.

其中最显着的药物提高重编程的是组蛋白脱乙酰1（HDAC1）抑制剂丙戊酸（VPA;皇甫等，2008人）中。 HDAC1的抑制似乎降低细胞状态之间的后生屏障和便于从一个状态到另一个的过渡。

Pluripotency in general is regulated by an interplay of different mechanisms, the most important of which we will outline in detail in the following. First, transcriptional regulation, i.e., activation or inhibition of target gene activity by specific transcription factors, controls the expression of master regulators of pluripotency or differentiation. A second layer of control consists in DNA methylation of promoters of genes. Finally, the organization of chromatin in active or repressive structures represents the third mechanism.

多能性，一般是通过不同的机制，这是最重要的，我们将详细概述在下面的相互作用调节。首先，转录调控，即激活或者通过特异性转录因子抑制靶基因的活性，控制多能性或分化的主调节器的表达。控制的第二层包括在基因的启动子的DNA甲基化。最后，染色质的活性或镇压结构的组织代表了第三种机制。

The core transcriptional regulatory circuitry of pluripotency in human embryonic stem cells (hESCs) was first established by Boyer et al. (2005) and contained the master regulators of pluripotency OCT4, SOX2, and NANOG. These three transcription factors were found to interact in a mutually- and auto-activating fashion thereby promoting and maintaining pluripotency (Boyer et al., 2005; Loh et al., 2006). This regulatory circuitry has been extended in further studies to yield different larger networks regulating pluripotency (Ivanova et al., 2006; Zhou et al., 2007; Chavez et al., 2009).

在人胚胎干细胞（胚胎干细胞）的核心转录调节多能性的电路首先由Boyer等建立的。 （2005）及其中的多能性OCT4，SOX2，NANOG和的主调节器。这三个转录因子中发现了一个mutually-和自动激活方式，从而促进和维持多能性进行交互（Boyer等，2005; Loh等人，2006）。一直延续进一步研究这种监管电路来产生不同的更大的网络调控多能性（伊万诺娃等人，2006; Zhou等，2007;查韦斯等，2009）。

DNA methylation of regulatory sequences, which silences gene promoters, is one of the known mechanisms in epigenetic regulation. This methylation is a major hindrance in reprogramming, because methylation marks cannot easily be removed, although there is evidence for active demethylation in reprogramming cells (Bhutani et al., 2011) which we will further discuss below.

调控序列的DNA甲基化，这沉默基因启动子，是在表观遗传调控已知的机制之一。这种甲基化是重编程的一个主要障碍，因为甲基化标记不易被删除，但有证据表明在重编程细胞的活性去甲基化（不丹等，2011），我们将进一步讨论如下。

With the advent of next generation sequencing techniques there is a wealth of data accumulating on DNA methylations (“methylomes”) in different cell types (Lister et al., 2009, 2011; Laurent et al., 2010). These studies reported large differences between ES/iPS and differentiated cells in the methylation states of promoters of key pluripotency and developmental genes. Moreover, they identified a very slow reprogramming of methylation states with aberrant methylation persisting in reprogramming cells, which can thus be distinguished from fully reprogrammed or ES cells.

随着新一代测序技术的出现有丰富的数据累积对DNA甲基化的（“methylomes”）在不同的细胞类型（李斯特等人，2009年，2011;。洛朗等，2010）。这些研究报告的关键多能性和发育基因的启动子甲基化状态ES/ iPS细胞与分化的细胞之间的巨大差异。此外，他们还确定了重编程细胞，因此可以从完全重新编程或ES细胞区分开来的甲基化状态与异常甲基化长期存在的一个非常缓慢的重新编程。