Silencing is noisy: population and cell level noise in telomere-adjacent genes is dependent on telomere position and sir2.
Silencing is noisy: population and cell level noise in telomere-adjacent genes is dependent on telomere position and sir2.
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DOI：
10.1371/journal.pgen.1004436
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发表时间：
2014-07
期刊：
影响因子：
4.5
通讯作者：
Berman J
中科院分区：
文献类型：
--
作者：
Anderson MZ;Gerstein AC;Wigen L;Baller JA;Berman J
细胞间基因表达噪声被认为是产生表型多样性的重要机制。此外，端粒区是基因扩增的主要位点，被认为是遗传多样性的驱动因素。在这里，我们发现单个亚端粒TLO基因在细胞水平和群体水平上都表现出转录和蛋白质水平的增加变异。细胞间的变异，被称为端粒邻近基因表达噪声（TAGEN），主要是内在噪声，并依赖于基因组位置：当TLO基因在异位的内部位点表达时，噪声降低，而当非端粒基因在端粒邻近位点表达时，噪声升高。这种位置依赖的TAGEN也依赖于Sir2p，一种依赖NAD+的组蛋白去乙酰化酶。最后，我们发现端粒沉默和TAGEN紧密相连，并以顺式方式调节：选择沉默或激活TLO邻近的URA3基因会导致邻近TLO的噪声降低，而其他TLO基因则不会。这为计算预测提供了实验支持，即在沉默和活跃染色质状态之间转换的能力对细胞间噪声有主要影响。此外，它还表明，这些变化分别影响每个端粒的表达变异程度。基因多样性通常在染色体端粒处很高，染色体端粒是基因容易扩增和修饰的地方。表型多样性，例如，在给定条件下的生长特性，受到同质环境中细胞间基因表达的随机变化的影响。我们的研究发现，单个亚端粒基因在单个群体内的细胞之间以及在不同的亚群体之间表现出高度的基因表达变异性。细胞间变异，称为端粒邻近基因表达噪声（TAGEN），影响单个端粒基因。我们发现经典的端粒沉默和TAGEN紧密相连，两者都依赖于端粒和Sir2染色质修饰酶的接近。此外，两者都在DNA水平上受到局部协调调节：在转录持续沉默或激活的端粒上，表达变异性水平降低。这项工作为预测随机染色质沉默和每个端粒表达可塑性之间的关系的计算工作提供了实验支持。此外，它表明这些变化影响端粒邻近位点的细胞间噪声的程度。
Cell-to-cell gene expression noise is thought to be an important mechanism for generating phenotypic diversity. Furthermore, telomeric regions are major sites for gene amplification, which is thought to drive genetic diversity. Here we found that individual subtelomeric TLO genes exhibit increased variation in transcript and protein levels at both the cell-to-cell level as well as at the population-level. The cell-to-cell variation, termed Telomere-Adjacent Gene Expression Noise (TAGEN) was largely intrinsic noise and was dependent upon genome position: noise was reduced when a TLO gene was expressed at an ectopic internal locus and noise was elevated when a non-telomeric gene was expressed at a telomere-adjacent locus. This position-dependent TAGEN also was dependent on Sir2p, an NAD+-dependent histone deacetylase. Finally, we found that telomere silencing and TAGEN are tightly linked and regulated in cis: selection for either silencing or activation of a TLO-adjacent URA3 gene resulted in reduced noise at the neighboring TLO but not at other TLO genes. This provides experimental support to computational predictions that the ability to shift between silent and active chromatin states has a major effect on cell-to-cell noise. Furthermore, it demonstrates that these shifts affect the degree of expression variation at each telomere individually. Genetic diversity is often high at telomeres, the chromosome ends where genes are readily amplified and modified. Phenotypic diversity, e.g., growth properties under a given condition, is affected by stochastic variations in gene expression exhibited among cells in a homogenous environment. Our studies found that individual subtelomeric genes show high variability of gene expression both between cells within a single population and also between separate sub-populations. Cell-to-cell variation, termed Telomere-Adjacent Gene Expression Noise (TAGEN), affected single telomeric genes. We found that classical telomeric silencing and TAGEN are tightly linked, with both being dependent upon proximity to telomeres and the Sir2 chromatin modifying enzyme. In addition, both are coordinately regulated locally—at the DNA level: at a telomere with transcription that is continually silenced or activated, the level of expression variability is reduced. This work provides experimental support for computational work that predicted this relationship between stochastic chromatin silencing and expression plasticity at each telomere individually. Furthermore, it demonstrates that these shifts affect the degree of cell-to cell noise of telomere-adjacent loci.
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影响因子：
8.8
作者：
Chen M;Licon K;Otsuka R;Pillus L;Ideker T
通讯作者：
Ideker T
影响因子：
30.8
作者：
Becskei, A;Kaufmann, BB;van Oudenaarden, A
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通讯作者：
Berman, Judith
影响因子：
2.6
作者：
Gerami-Nejad, M;Berman, J;Gale, CA
通讯作者：
Gale, CA