High level and nature of transcriptional noise in yeast cells [MNase-Seq]

“Biological noise” is defined as functionally insignificant events that occur in living cells due to imperfect fidelity of biological processes. Distinguishing between biological function and biological noise is often difficult, and experiments to measure biological noise have not been performed. Here, we measure biological noise in yeast cells by analyzing chromatin structure and transcription of an 18 kb region of DNA whose sequence was randomly generated and hence is functionally irrelevant. Nucleosome occupancy on random-sequence DNA is comparable to that on yeast genomic DNA. However, nucleosome-depleted regions are much less frequent, and there are fewer well-positioned nucleosomes and shorter nucleosome arrays. Steady-state levels of RNAs expressed from random-sequence DNA are comparable to those of yeast mRNAs, although transcription and mRNA decay rates are at higher levels. Transcriptional initiation (5’ ends) from random-sequence DNA occurs at numerous sites at low levels, indicating very low intrinsic specificity of the Pol II machinery. In contrast, poly(A) profiles (relative levels and clustering of 3’ isoforms) of random-sequence RNAs are roughly comparable to those of endogenous yeast RNAs, which are restricted to 3’ untranslated regions. RNAs expressed from random-sequence DNA show higher cell-to-cell variability than RNAs expressed from yeast genomic DNA, suggesting that functional elements limit the variability among individual cells within a population. These observations indicate that transcriptional noise occurs at high levels in yeast, and they provide insight into how chromatin and transcription patterns arise from the evolved yeast genome.“生物噪声（Biological noise）被定义为活细胞内因生物过程保真度不完善而产生的功能无关事件。区分生物功能与生物噪声通常极具挑战，且目前尚未开展针对生物噪声的定量检测实验。本研究通过分析一段序列随机生成、因此功能无关的18千碱基对（kb）DNA区域的染色质结构与转录情况，对酵母细胞内的生物噪声进行定量检测。随机序列DNA上的核小体占据率与酵母基因组DNA上的水平相当，但核小体缺失区域的出现频率显著更低，且定位良好的核小体数量更少、核小体阵列长度更短。尽管转录速率与mRNA衰变速率均处于较高水平，但随机序列DNA表达的RNA稳态水平与酵母mRNA的稳态水平相当。随机序列DNA的转录起始（5'端）广泛分布于众多位点且表达水平较低，表明RNA聚合酶II（Pol II）转录机器的内在特异性极低。与之相反，随机序列RNA的poly(A)谱（3'异构体的相对丰度与聚集模式）与内源酵母RNA大致相当，且后者的poly(A)位点均局限于3'非翻译区（3'UTR）。随机序列DNA表达的RNA相较于酵母基因组DNA表达的RNA，展现出更高的细胞间异质性，这表明功能元件会限制种群内单个细胞之间的表达差异。上述观测结果表明，酵母细胞内的转录噪声处于较高水平，同时也为解析进化而来的酵母基因组如何塑造染色质与转录模式提供了新的认知视角。