TIF1β regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner
TIF1β regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner
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DOI：
10.1073/pnas.0907601107
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发表时间：
2010-06-15
影响因子：
11.1
通讯作者：
Asashima, Makoto
中科院分区：
文献类型：
--
作者：
Seki, Yasuhiro;Kurisaki, Akira;Asashima, Makoto
在未分化的胚胎干细胞中特异表达的转录因子组成的转录网络参与了胚胎干细胞多能性的调控。然而，在ES细胞分化过程中，负责自我更新、维持多能性和谱系特化的分子机制仍不清楚。这项研究的结果表明，磷酸化依赖的染色质松弛因子，转录中介因子-1 β（TIF 1 β），是一个独特的调节器的多能性的ES细胞和调节Oct 3/4依赖的转录磷酸化依赖的方式。在多能小鼠ES细胞中，TIF 1 β在C-末端丝氨酸824处特异性磷酸化，其先前已显示诱导染色质松弛。磷酸化的TIF 1 β部分共定位于活化的染色质标记物，并与多能特异性转录因子Oct 3/4和转换缺陷/蔗糖非发酵、ATP依赖性染色质重塑复合物Smarcad 1、Brg-1和BAF 155的亚基形成复合物，所有这些都是ES特异性染色质重塑复合物esBAF的组分。磷酸化的TIF 1 β特异性诱导ES细胞特异性基因，并使小鼠ES细胞中的未分化状态得以长期维持。此外，TIF 1 β以磷酸化依赖的方式调节体细胞的重编程过程。我们的研究结果表明，TIF 1 β提供了一个磷酸化依赖的，双向的平台，为特定的转录因子和染色质重塑酶，调节细胞分化过程和干细胞的多能性。
Transcription networks composed of various transcriptional factors specifically expressed in undifferentiated embryonic stem (ES) cells have been implicated in the regulation of pluripotency in ES cells. However, the molecular mechanisms responsible for self-renewal, maintenance of pluripotency, and lineage specification during differentiation of ES cells are still unclear. The results of this study demonstrate that a phosphorylation-dependent chromatin relaxation factor, transcriptional intermediary factor-1 beta (TIF1 beta), is a unique regulator of the pluripotency of ES cells and regulates Oct3/4-dependent transcription in a phosphorylation-dependent manner. TIF1 beta is specifically phosphorylated in pluripotent mouse ES cells at the C-terminal serine 824, which has been previously shown to induce chromatin relaxation. Phosphorylated TIF1 beta is partially colocalized at the activated chromatin markers, and forms a complex with the pluripotency-specific transcription factor Oct3/4 and subunits of the switching defective/sucrose nonfermenting, ATP-dependent chromatin remodeling complex, Smarcad1, Brg-1, and BAF155, all of which are components of an ES-specific chromatin remodeling complex, esBAF. Phosphorylated TIF1 beta specifically induces ES cell-specific genes and enables prolonged maintenance of an undifferentiated state in mouse ES cells. Moreover, TIF1 beta regulates the reprogramming process of somatic cells in a phosphorylation-dependent manner. Our results suggest that TIF1 beta provides a phosphorylation-dependent, bidirectional platform for specific transcriptional factors and chromatin remodeling enzymes that regulate the cell differentiation process and the pluripotency of stem cells.