Quantitative control of noise in mammalian gene expression by dynamic histone regulation.
Quantitative control of noise in mammalian gene expression by dynamic histone regulation.
复制标题
通过动态组蛋白调节定量控制哺乳动物基因表达中的噪声
DOI：
10.7554/elife.65654
复制
发表时间：
2021-08-11
期刊：
影响因子：
7.7
通讯作者：
Huang W
中科院分区：
文献类型：
--
作者：
Tan D;Chen R;Mo Y;Gu S;Ma J;Xu W;Lu X;He H;Jiang F;Fan W;Wang Y;Chen X;Huang W
基因表达的波动（“噪音”）对于哺乳动物细胞过程至关重要。许多机制促成了其起源，但由单一转录激活剂诱导的大波动背后的机制仍然难以捉摸。在这里，我们通过研究单细胞中转录激活因子结合、组蛋白调节抑制剂、染色质可及性以及 mRNA 和蛋白质水平的动态调节来探讨假定的机制。使用光诱导表达系统，我们证明转录激活剂可以与双功能共激活剂/组蛋白乙酰转移酶 CBP/p300 形成相互作用。这种相互作用导致 H3K27ac、染色质可及性和转录存在显着的异质性。 CBP/p300 和 HDAC4/5 的同时减弱降低了内源基因表达的异质性，表明这种机制是普遍的。我们进一步发现，转录激活剂结合的脉冲宽度调制降低了噪声，这可能是表观遗传状态交替的结果。我们的研究结果提出了合成和内源基因表达系统中噪音调节的机制。
Fluctuation ('noise') in gene expression is critical for mammalian cellular processes. Numerous mechanisms contribute to its origins, yet the mechanisms behind large fluctuations that are induced by single transcriptional activators remain elusive. Here, we probed putative mechanisms by studying the dynamic regulation of transcriptional activator binding, histone regulator inhibitors, chromatin accessibility, and levels of mRNAs and proteins in single cells. Using a light-induced expression system, we showed that the transcriptional activator could form an interplay with dual functional co-activator/histone acetyltransferases CBP/p300. This interplay resulted in substantial heterogeneity in H3K27ac, chromatin accessibility, and transcription. Simultaneous attenuation of CBP/p300 and HDAC4/5 reduced heterogeneity in the expression of endogenous genes, suggesting that this mechanism is universal. We further found that the noise was reduced by pulse-wide modulation of transcriptional activator binding possibly as a result of alternating the epigenetic states. Our findings suggest a mechanism for the modulation of noise in synthetic and endogenous gene expression systems.