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Abstract：
Pioneer transcription factors are proteins with a dual function. First, they regulate transcription by binding to nucleosome-free DNA regulatory elements. Second, they bind to DNA while wrapped around histone proteins in the chromatin and mediate chromatin opening. The molecular mechanisms that connect the two functions are yet to be discovered. In recent years, pioneer factors received increased attention mainly because of their crucial role in promoting cell fate transitions that could be used for regenerative therapies. For example, the three factors required to induce pluripotency in somatic cells, Oct4, Sox2, and Klf4 were classified as pioneer factors and studied extensively. With this increased attention, several structures of complexes between pioneer factors and chromatin structural units (nucleosomes) have been resolved experimentally. Furthermore, experimental and computational approaches have been designed to study two unresolved, key scientific questions: First, do pioneer factors induce directly local opening of nucleosomes and chromatin fibers upon binding? And second, how do the unstructured tails of the histones impact the structural dynamics involved in such conformational transitions? Here we review the current knowledge about transcription factor-induced nucleosome dynamics and the role of the histone tails in this process. We discuss what is needed to bridge the gap between the static views obtained from the experimental structures and the key structural dynamic events in chromatin opening. Finally, we propose that integrating nuclear magnetic resonance spectroscopy with molecular dynamics simulations is a powerful approach to studying pioneer factor-mediated dynamics of nucleosomes and perhaps small chromatin fibers using native DNA sequences.
摘要：
先锋转录因子是具有双重功能的蛋白质。首先,它们通过与无核小体的DNA调节元件结合来调节转录。第二,它们与DNA结合，同时包裹染色质中的组蛋白并介导染色质开放。连接这两种功能的分子机制尚未被发现。近年来,先驱因子受到越来越多的关注,主要是因为它们在促进可用于再生疗法的细胞命运转变方面发挥了关键作用.例如,在体细胞中诱导多能性所需的三个因素，Oct4，Sox2和Klf4被归类为先驱因子，并进行了广泛的研究。随着注意力的增加，先驱因子和染色质结构单元（核小体）之间的几种复合物结构已通过实验解析。此外，实验和计算方法被设计来研究两个未解决的问题，关键的科学问题：首先，先驱因子在结合后会直接诱导核小体和染色质纤维的局部开放吗？第二，组蛋白的非结构化尾部如何影响这种构象转变所涉及的结构动力学？在这里，我们回顾了有关转录因子诱导的核小体动力学以及组蛋白尾部在这一过程中的作用的最新知识。我们讨论了弥合从实验结构获得的静态视图与染色质开放中的关键结构动态事件之间的差距所需要的东西。最后,我们认为，将核磁共振波谱与分子动力学模拟相结合是使用天然DNA序列研究先锋因子介导的核小体动力学和可能的小染色质纤维动力学的有效方法。
