Dynamic switching of transcriptional regulators between two distinct low-mobility chromatin states
Dynamic switching of transcriptional regulators between two distinct low-mobility chromatin states
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DOI：
10.1126/sciadv.ade1122
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发表时间：
2023-06-16
期刊：
影响因子：
13.6
通讯作者：
Hager，Gordon L.
中科院分区：
文献类型：
--
作者：
Wagh，Kaustubh;Stavreva，Diana A.;Hager，Gordon L.
染色质动力学如何与转录活性相关仍然知之甚少。使用单分子追踪并结合机器学习，我们发现组蛋白 H2B 和多个染色质结合转录调节因子表现出两种不同的低迁移率状态。配体激活导致类固醇受体在最低迁移率状态下结合的倾向显着增加。突变分析表明，在最低迁移率状态下与染色质的相互作用需要完整的 DNA 结合域和寡聚化域。这些状态并不像之前认为的那样在空间上分离，但单个 H2B 和结合的 TF 分子可以在几秒的时间尺度上动态地在它们之间切换。具有不同迁移率的单结合 TF 分子表现出不同的停留时间分布，表明 TF 的迁移率与其结合动力学密切相关。总之，我们的结果确定了两种独特且不同的低迁移率状态，它们似乎代表了哺乳动物细胞中转录激活的常见途径。
How chromatin dynamics relate to transcriptional activity remains poorly understood. Using single-molecule tracking, coupled with machine learning, we show that histone H2B and multiple chromatin-bound transcriptional regulators display two distinct low-mobility states. Ligand activation results in a marked increase in the propensity of steroid receptors to bind in the lowest-mobility state. Mutational analysis revealed that interactions with chromatin in the lowest-mobility state require an intact DNA binding domain and oligomerization domains. These states are not spatially separated as previously believed, but individual H2B and bound-TF molecules can dynamically switch between them on time scales of seconds. Single bound-TF molecules with different mobilities exhibit different dwell time distributions, suggesting that the mobility of TFs is intimately coupled with their binding dynamics. Together, our results identify two unique and distinct low-mobility states that appear to represent common pathways for transcription activation in mammalian cells.