Nonspecific transcription factor binding can reduce noise in the expression of downstream proteins
Nonspecific transcription factor binding can reduce noise in the expression of downstream proteins
复制标题
非特异性转录因子结合可以减少下游蛋白质表达中的噪音
作者：
Mohammad Soltani;Pavol Bokes;Z. Fox;Abhyudai Singh
转录因子（tf）与细胞内DNA和伴侣蛋白上的许多结合位点相互作用。我们研究了与这些诱饵结合位点的非特异性结合/解结合如何影响随机基因表达引起的TF拷贝数随机波动的幅度和时间尺度。一个随机模型的TF基因表达，连同诱饵位点相互作用制定。总（结合和未结合）和自由（未结合）TF水平的分布是在生理学相关假设下通过解析求解化学主方程得出的。我们的研究结果表明，增加诱饵结合侧的数量大大降低了自由TF拷贝数的随机性。从TF自相关函数可以看出，随着模型参数的变化，诱饵点可以增强或缩短TF波动的时间尺度。为了了解TF丰度中的噪声是如何向下游传播的，模型中包含了一个TF靶基因。有趣的是，我们发现靶基因表达中的噪声随着线性TF靶蛋白剂量反应的诱饵位点的增加而减少，即使在诱饵位点增强TF自相关时间的情况下也是如此。此外，非线性剂量响应会产生反直觉的噪声传输。总之，我们的研究强调了诱骗结合位点的分子隔离在单细胞水平上调节tf和靶蛋白的随机动力学中的关键作用。
Transcription factors (TFs) interact with a multitude of binding sites on DNA and partner proteins inside cells. We investigate how nonspecific binding/unbinding to such decoy binding sites affects the magnitude and time-scale of random fluctuations in TF copy numbers arising from stochastic gene expression. A stochastic model of TF gene expression, together with decoy site interactions is formulated. Distributions for the total (bound and unbound) and free (unbound) TF levels are derived by analytically solving the chemical master equation under physiologically relevant assumptions. Our results show that increasing the number of decoy binding sides considerably reduces stochasticity in free TF copy numbers. The TF autocorrelation function reveals that decoy sites can either enhance or shorten the time-scale of TF fluctuations depending on model parameters. To understand how noise in TF abundances propagates downstream, a TF target gene is included in the model. Intriguingly, we find that noise in the expression of the target gene decreases with increasing decoy sites for linear TF-target protein dose-responses, even in regimes where decoy sites enhance TF autocorrelation times. Moreover, counterintuitive noise transmissions arise for nonlinear dose-responses. In summary, our study highlights the critical role of molecular sequestration by decoy binding sites in regulating the stochastic dynamics of TFs and target proteins at the single-cell level.
登录
查看更多内容
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
Abhyudai Singh;B. Razooky;R. D. Dar;L. Weinberger
通讯作者：
Abhyudai Singh;B. Razooky;R. D. Dar;L. Weinberger
影响因子：
5.4
作者：
Singh, Abhyudai;Weinberger, Leor S.
通讯作者：
Weinberger, Leor S.
影响因子：
4.4
作者：
Gomez-Uribe, Carlos A.;Verghese, George C.
通讯作者：
Verghese, George C.
影响因子：
3.5
作者：
Bokes, Pavol;King, John R.;Loose, Matthew
通讯作者：
Loose, Matthew
DOI：
10.1073/pnas.95.26.15641
发表时间：
1998-12-22
影响因子：
11.1
作者：
Cook, DL;Gerber, LN;Tapscott, SJ
通讯作者：
Tapscott, SJ