Pluripotency maintenance mechanism of embryonic stem cells and reprogramming.
ABSTRACT Embryonic stem (ES) cells are derived from blastocysts and are pluripotent. This pluripotency has attracted the interest of numerous researchers, both to expand our fundamental understanding of developmental biology and also because of potential applications in regenerative medicine. Systems biological studies have demonstrated that the pivotal transcription factors form a network. There they activate pluripotency-associated genes, including themselves, while repressing the developmentally regulated genes through co-occupation with various protein complexes. The chromatin structure characteristic of ES cells also contributes to the maintenance of the network. In this review, I focus on recent advances in our understanding of the transcriptional network that maintains pluripotency in mouse ES cells.
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ABSTRACT: Elucidating how chromatin influences gene expression patterns and ultimately cell fate is fundamental to understanding development and disease. The histone variant H2AZ has emerged as a key regulator of chromatin function and plays an essential but unknown role during mammalian development. Here, genome-wide analysis reveals that H2AZ occupies the promoters of developmentally important genes in a manner that is remarkably similar to that of the Polycomb group (PcG) protein Suz12. By using RNAi, we demonstrate a role for H2AZ in regulating target gene expression, find that H2AZ and PcG protein occupancy is interdependent at promoters, and further show that H2AZ is necessary for ES cell differentiation. Notably, H2AZ occupies a different subset of genes in lineage-committed cells, suggesting that its dynamic redistribution is necessary for cell fate transitions. Thus, H2AZ, together with PcG proteins, may establish specialized chromatin states in ES cells necessary for the proper execution of developmental gene expression programs.Cell 12/2008; 135(4):649-61. · 31.96 Impact Factor
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ABSTRACT: Kyoto University (京都大学) 0048 新制・課程博士 博士(医学) 甲第14040号 医博第3256号 新制/医/969 UT51-2008-F432 2008-05-23 京都大学大学院医学研究科内科系専攻 (主査)教授 篠原 隆司, 教授 中畑 龍俊, 教授 中辻 憲夫 学位規則第4条第1項該当01/2008;
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ABSTRACT: MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3' untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3' untranslated region.Nature 10/2008; 455(7216):1124-8. · 38.60 Impact Factor