Pluripotency associated genes are reactivated by chromatin-modifying agents in neurosphere cells
Pluripotency associated genes are reactivated by chromatin-modifying agents in neurosphere cells
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DOI：
10.1634/stemcells.2007-0649
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发表时间：
2008-04-01
期刊：
影响因子：
5.2
通讯作者：
Zenke, Martin
中科院分区：
文献类型：
--
作者：
Ruau, David;Ensenat-Waser, Roberto;Zenke, Martin
干细胞中的染色质结构决定了基因表达的模式，从而决定了细胞的身份和命运。染色质修饰剂甲硫氨酸（TSA）和5-氮杂-2 '-脱氧胞苷（AzaC）分别影响组蛋白乙酰化和DNA甲基化，从而影响染色质结构和基因表达。在我们以前的工作中，我们证明了TSA/AzaC处理神经球细胞诱导体内造血活性，这是长期的，多谱系的，可移植的。在这里，我们分析了TSA/AzaC诱导的基因表达的变化，通过全球基因表达谱。TSA/AzaC引起基因的上调和下调，而不增加表达基因的总数。染色体分析显示TSA/AzaC对特定染色体或染色体区域没有影响的热点。层次聚类分析揭示了TSA/AzaC处理的神经球细胞、胚胎干细胞和造血干细胞之间的共同基因表达模式。此外，我们的分析确定了TSA/AzaC在神经球细胞中诱导的几个干细胞基因和多能性相关基因，包括Cd 34，Cd 133，Oct 4，Nanog，Klf 4，Bex 1和Dppa家族成员Dppa 2，3，4和5。Sox 2和c-Myc在神经球细胞中组成型表达。我们提出了一个模型，其中TSA/AzaC，通过去除表观遗传抑制，诱导几个干细胞和多能性相关基因的重新激活，它们的协调表达扩大了体细胞前体细胞的分化潜力。
Chromatin architecture in stem cells determines the pattern of gene expression and thereby cell identity and fate. The chromatin-modifying agents trichostatin A (TSA) and 5-Aza-2'-deoxycytidine (AzaC) affect histone acetylation and DNA methylation, respectively, and thereby influence chromatin structure and gene expression. In our previous work, we demonstrated that TSA/AzaC treatment of neurosphere cells induces hematopoietic activity in vivo that is long-term, multilineage, and transplantable. Here, we have analyzed the TSA/AzaC-induced changes in gene expression by global gene expression profiling. TSA/AzaC caused both up- and downregulation of genes, without increasing the total number of expressed genes. Chromosome analysis showed no hot spot of TSA/AzaC impact on a particular chromosome or chromosomal region. Hierarchical cluster analysis revealed common gene expression patterns among neurosphere cells treated with TSA/AzaC, embryonic stem (ES) cells, and hematopoietic stem cells. Furthermore, our analysis identified several stem cell genes and pluripotency-associated genes that are induced by TSA/AzaC in neurosphere cells, including Cd34, Cd133, Oct4, Nanog, Klf4, Bex1, and the Dppa family members Dppa2, 3, 4, and 5. Sox2 and c-Myc are constitutively expressed in neurosphere cells. We propose a model in which TSA/AzaC, by removal of epigenetic inhibition, induces the reactivation of several stem cell and pluripotency-associated genes, and their coordinate expression enlarges the differentiation potential of somatic precursor cells.