The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells.
The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells.
复制标题
DOI：
10.7554/elife.22631
复制
发表时间：
2017-03-13
期刊：
影响因子：
7.7
通讯作者：
Klose RJ
中科院分区：
文献类型：
--
作者：
King HW;Klose RJ
先锋转录因子识别并结合难以接近的染色质中的靶序列，在整个发育和细胞重编程过程中建立新的转录网络。在此过程中，先锋因子建立了一种可接近的染色质状态，以促进额外的转录因子结合，但目前尚不清楚不同的先锋因子如何实现这一目标。在这里，我们发现多能性相关先锋因子 OCT4 与染色质结合，从而影响小鼠胚胎干细胞的形状可及性、转录因子共结合和调节元件功能。 OCT4 结合位点的染色质可及性需要染色质重塑剂 BRG1，OCT4 将其招募到这些位点以支持额外的转录因子结合和多能性相关转录组的表达。此外，BRG1 在塑造 OCT4 结合方面的要求反映了这些靶位点在细胞重编程和早期小鼠发育过程中的使用方式。总之，这揭示了染色质重塑剂在促进先驱因子 OCT4 的活性和调节多能性网络方面的独特要求。 DOI：http://dx.doi.org/10.7554/eLife.22631.001 您体内的所有细胞都以 DNA 编码的基因形式包含相同的遗传信息。然而，细胞以不同的方式使用这些信息，因此 DNA 中各个基因的活性可能因细胞而异。这使得相同的细胞变得彼此不同并适应不断变化的环境。一组称为转录因子的蛋白质通过与 DNA 上的特定位点结合来控制某些基因的活性。然而，这并不是一个简单的过程，因为人类和其他动物细胞中的 DNA 通常与称为核小体的结构相关，而核小体可以阻止 DNA 的进入。先锋转录因子，例如 OCT4，是一组特定的转录因子，尽管存在核小体，但仍可以附着在 DNA 上，但目前尚不清楚这是如何实现的。一旦先驱转录因子附着到 DNA 上，它们就可以帮助其他转录因子与其结合。金等人。研究了小鼠胚胎干细胞中的 OCT4，以研究它如何充当先锋转录因子并控制基因活性。实验表明，当 OCT4 缺失时，其他几种转录因子就会失去与 DNA 结合的能力。这导致细胞内基因活性发生广泛变化，这似乎是由于其他转录因子无法穿过核小体附着在 DNA 上。进一步的实验表明，OCT4 需要一种名为 BRG1 的蛋白质才能充当先锋转录因子。 BRG1 是一种能够移动和去除（重塑）附着在 DNA 上的核小体的酶，表明正常的转录因子结合需要这种活性。下一个挑战是研究正常基因活性和细胞身份所需的其他先锋转录因子是否也需要 BRG1 或类似的酶。这很重要，因为许多重塑核小体的酶在癌症等人类疾病中被破坏，细胞失去了正常的身份。 DOI：http://dx.doi.org/10.7554/eLife.22631.002
Pioneer transcription factors recognise and bind their target sequences in inaccessible chromatin to establish new transcriptional networks throughout development and cellular reprogramming. During this process, pioneer factors establish an accessible chromatin state to facilitate additional transcription factor binding, yet it remains unclear how different pioneer factors achieve this. Here, we discover that the pluripotency-associated pioneer factor OCT4 binds chromatin to shape accessibility, transcription factor co-binding, and regulatory element function in mouse embryonic stem cells. Chromatin accessibility at OCT4-bound sites requires the chromatin remodeller BRG1, which is recruited to these sites by OCT4 to support additional transcription factor binding and expression of the pluripotency-associated transcriptome. Furthermore, the requirement for BRG1 in shaping OCT4 binding reflects how these target sites are used during cellular reprogramming and early mouse development. Together this reveals a distinct requirement for a chromatin remodeller in promoting the activity of the pioneer factor OCT4 and regulating the pluripotency network. DOI: http://dx.doi.org/10.7554/eLife.22631.001 All cells in your body contain the same genetic information in the form of genes encoded within DNA. Yet, cells use this information in different ways so that the activities of individual genes within that DNA can vary from cell to cell. This allows identical cells to become different to each other and to adapt to changing circumstances. A group of proteins called transcription factors control the activity of certain genes by binding to specific sites on DNA. However, this isn’t a straightforward process because DNA in human and other animal cells is usually associated with structures called nucleosomes that can block access to the DNA. Pioneer transcription factors, such as OCT4, are a specific group of transcription factors that can attach to DNA in spite of the nucleosomes, but it’s not clear how this is possible. Once pioneer transcription factors attach to DNA they can help other transcription factors to bind alongside them. King et al. studied OCT4 in stem cells from mouse embryos to investigate how it is able to act as a pioneer transcription factor and control gene activity. The experiments show that several other transcription factors lose the ability to bind to DNA when OCT4 is absent. This leads to widespread changes in gene activity in the cells, which seems to be due to other transcription factors being unable to get past the nucleosomes to attach to the DNA. Further experiments showed that OCT4 needs a protein called BRG1 in order to act as a pioneer transcription factor. BRG1 is an enzyme that is able to move and remove (remodel) nucleosomes attached to DNA, suggesting that normal transcription factor binding requires this activity. The next challenge is to investigate whether BRG1, or similar enzymes, are also needed by other pioneer transcription factors that are required for normal gene activity and cell identity. This will be important because many enzymes that remodel nucleosomes are disrupted in human diseases like cancer where cells lose their normal identity. DOI: http://dx.doi.org/10.7554/eLife.22631.002