Undifferentiated Embryonic Cell Transcription Factor 1 Regulates ESC Chromatin Organization and Gene Expression
Undifferentiated Embryonic Cell Transcription Factor 1 Regulates ESC Chromatin Organization and Gene Expression
复制标题
DOI：
10.1002/stem.497
复制
发表时间：
2010-10-01
期刊：
影响因子：
5.2
通讯作者：
Eggen, Bart J. L.
中科院分区：
文献类型：
--
作者：
Kooistra, Susanne M.;van den Boom, Vincent;Eggen, Bart J. L.
先前的研究表明，胚胎干细胞具有高动态和全局转录的染色质特性，这对胚胎干细胞的多能性和分化至关重要。在这里，我们证明了未分化胚胎细胞转录因子1 （UTF1）在调节ES细胞染色质结构中的作用。利用染色质免疫沉淀芯片分析，我们鉴定出bbb1700个UTF1靶基因与先前鉴定的Nanog、Oct4、Klf-4、c-Myc和Rex1靶基因显著重叠。基因表达谱显示，UTF1敲低导致大量基因表达增加，包括大量UTF1靶点。不管几种自我更新基因的表达是否增加，UTF1敲低（KD） ES细胞都依赖于白血病抑制因子（LIF）。然而，UTF1 KD ES细胞在二甲亚砜（DMSO）或liff退出后的分化受到干扰，并显示出增加的集落形成。UTF1 KD ES细胞表现出广泛的染色质去浓缩，反映在微球菌核酸酶（MNase）处理下核小体释放的急剧增加和UTF1靶基因MNase在UTF1 KD ES细胞中的敏感性增强。综上所述，我们的数据表明，UTF1是胚胎干细胞中一个关键的染色质成分，可以防止胚胎干细胞染色质去浓缩和基因异常表达；两者都是胚胎干细胞分化的必要条件。干细胞2010；28日:1703 - 1714
Previous reports showed that embryonic stem (ES) cells contain hyperdynamic and globally transcribed chromatin-properties that are important for ES cell pluripotency and differentiation. Here, we demonstrate a role for undifferentiated embryonic cell transcription factor 1 (UTF1) in regulating ES cell chromatin structure. Using chromatin immunoprecipitation-on-chip analysis, we identified >1,700 UTF1 target genes that significantly overlap with previously identified Nanog, Oct4, Klf-4, c-Myc, and Rex1 targets. Gene expression profiling showed that UTF1 knock down results in increased expression of a large set of genes, including a significant number of UTF1 targets. UTF1 knock down (KD) ES cells are, irrespective of the increased expression of several self-renewal genes, Leukemia inhibitory factor (LIF) dependent. However, UTF1 KD ES cells are perturbed in their differentiation in response to dimethyl sulfoxide (DMSO) or after LIF withdrawal and display increased colony formation. UTF1 KD ES cells display extensive chromatin decondensation, reflected by a dramatic increase in nucleosome release on micrococcal nuclease (MNase) treatment and enhanced MNase sensitivity of UTF1 target genes in UTF1 KD ES cells. Summarizing, our data show that UTF1 is a key chromatin component in ES cells, preventing ES cell chromatin decondensation, and aberrant gene expression; both essential for proper initiation of lineage-specific differentiation of ES cells. STEM CELLS 2010; 28: 1703-1714