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对小鼠和人类胚胎干细胞中活跃的顺式调控序列进行系统鉴定。

Systematic identification of cis-regulatory sequences active in mouse and human embryonic stem cells.

作者信息

Grskovic Marica, Chaivorapol Christina, Gaspar-Maia Alexandre, Li Hao, Ramalho-Santos Miguel

机构信息

Institute for Regeneration Medicine, University of California San Francisco, San Francisco, California, United States of America.

出版信息

PLoS Genet. 2007 Aug;3(8):e145. doi: 10.1371/journal.pgen.0030145.

Abstract

Understanding the transcriptional regulation of pluripotent cells is of fundamental interest and will greatly inform efforts aimed at directing differentiation of embryonic stem (ES) cells or reprogramming somatic cells. We first analyzed the transcriptional profiles of mouse ES cells and primordial germ cells and identified genes upregulated in pluripotent cells both in vitro and in vivo. These genes are enriched for roles in transcription, chromatin remodeling, cell cycle, and DNA repair. We developed a novel computational algorithm, CompMoby, which combines analyses of sequences both aligned and non-aligned between different genomes with a probabilistic segmentation model to systematically predict short DNA motifs that regulate gene expression. CompMoby was used to identify conserved overrepresented motifs in genes upregulated in pluripotent cells. We show that the motifs are preferentially active in undifferentiated mouse ES and embryonic germ cells in a sequence-specific manner, and that they can act as enhancers in the context of an endogenous promoter. Importantly, the activity of the motifs is conserved in human ES cells. We further show that the transcription factor NF-Y specifically binds to one of the motifs, is differentially expressed during ES cell differentiation, and is required for ES cell proliferation. This study provides novel insights into the transcriptional regulatory networks of pluripotent cells. Our results suggest that this systematic approach can be broadly applied to understanding transcriptional networks in mammalian species.

摘要

了解多能细胞的转录调控具有根本重要性,并且将极大地为旨在指导胚胎干细胞(ES细胞)分化或重编程体细胞的努力提供信息。我们首先分析了小鼠ES细胞和原始生殖细胞的转录谱,并鉴定了在体外和体内多能细胞中上调的基因。这些基因在转录、染色质重塑、细胞周期和DNA修复中发挥的作用富集。我们开发了一种新颖的计算算法CompMoby,它将不同基因组之间比对和未比对序列的分析与概率分割模型相结合,以系统地预测调控基因表达的短DNA基序。CompMoby用于鉴定在多能细胞中上调的基因中保守的过度表达基序。我们表明,这些基序以序列特异性方式在未分化的小鼠ES细胞和胚胎生殖细胞中优先活跃,并且它们可以在内源启动子的背景下起增强子的作用。重要的是,这些基序的活性在人类ES细胞中是保守的。我们进一步表明,转录因子NF-Y特异性结合其中一个基序,在ES细胞分化过程中差异表达,并且是ES细胞增殖所必需的。这项研究为多能细胞的转录调控网络提供了新的见解。我们的结果表明,这种系统方法可广泛应用于理解哺乳动物物种的转录网络。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a94/1959399/2293d90f4fc7/pgen.0030145.g001.jpg

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