Power-law behavior of transcription factor dynamics at the single-molecule level implies a continuum affinity model
Power-law behavior of transcription factor dynamics at the single-molecule level implies a continuum affinity model
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DOI：
10.1093/nar/gkab072
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发表时间：
2021-02-17
影响因子：
14.9
通讯作者：
Hager, Gordon L.
中科院分区：
文献类型：
--
作者：
Garcia, David A.;Fettweis, Gregory;Hager, Gordon L.
单分子跟踪（SMT）允许研究转录因子（TF）在细胞核中的动力学，提供有关这些蛋白质在核环境中的扩散和结合行为的重要信息。通过SMT获得的大多数TF的停留时间分布似乎遵循双指数行为。这被归因于两个离散的TF群体-一个非特异性结合染色质，另一个特异性结合靶位点，如数十年的生物化学研究所暗示的。然而，新兴的研究提出了驻留时间分布的替代模型，表明存在两个以上的TF群体（多指数分布），甚至完全没有离散状态（幂律分布）。在这里，我们提出了一个分析管道，以评估哪个模型最好地解释SMT数据。我们发现，广泛的TF（包括糖皮质激素受体，雌激素受体，FOXA 1，CTCF）遵循幂律分布的停留时间，模糊了非特异性和特异性结合之间的时间线，这表明生产性结合可能涉及更长的结合事件比以前认为的。从这些观察，我们提出了一个连续的亲和力模型来解释TF动力学，这是一致的复杂的相互作用的TF与多个核结构域，以及结合和搜索的染色质模板。
Single-molecule tracking (SMT) allows the study of transcription factor (TF) dynamics in the nucleus, giving important information regarding the diffusion and binding behavior of these proteins in the nuclear environment. Dwell time distributions obtained by SMT for most TFs appear to follow bi-exponential behavior. This has been ascribed to two discrete populations of TFs-one non-specifically bound to chromatin and another specifically bound to target sites, as implied by decades of biochemical studies. However, emerging studies suggest alternate models for dwell-time distributions, indicating the existence of more than two populations of TFs (multiexponential distribution), or even the absence of discrete states altogether (power-law distribution). Here, we present an analytical pipeline to evaluate which model best explains SMT data. We find that a broad spectrum of TFs (including glucocorticoid receptor, oestrogen receptor, FOXA1, CTCF) follow a power-law distribution of dwell-times, blurring the temporal line between non-specific and specific binding, suggesting that productive binding may involve longer binding events than previously believed. From these observations, we propose a continuum of affinities model to explain TF dynamics, that is consistent with complex interactions of TFs with multiple nuclear domains as well as binding and searching on the chromatin template.