Jeffers Tess E, Lieb Jason D
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA.
Genome Res. 2017 Jan;27(1):75-86. doi: 10.1101/gr.208173.116. Epub 2016 Nov 14.
Nucleosomes have structural and regulatory functions in all eukaryotic DNA-templated processes. The position of nucleosomes on DNA and the stability of the underlying histone-DNA interactions affect the access of regulatory proteins to DNA. Both stability and position are regulated through DNA sequence, histone post-translational modifications, histone variants, chromatin remodelers, and transcription factors. Here, we explored the functional implications of nucleosome properties on gene expression and development in Caenorhabditis elegans embryos. We performed a time-course of micrococcal nuclease (MNase) digestion and measured the relative sensitivity or resistance of nucleosomes throughout the genome. Fragile nucleosomes were defined by nucleosomal DNA fragments that were recovered preferentially in early MNase-digestion time points. Nucleosome fragility was strongly and positively correlated with the AT content of the underlying DNA sequence. There was no correlation between promoter nucleosome fragility and the levels of histone modifications or histone variants. Genes with fragile nucleosomes in their promoters tended to be lowly expressed and expressed in a context-specific way, operating in neuronal response, the immune system, and stress response. In addition to DNA-encoded nucleosome fragility, we also found fragile nucleosomes at locations where we expected to find destabilized nucleosomes, for example, at transcription factor binding sites where nucleosomes compete with DNA-binding factors. Our data suggest that in C. elegans promoters, nucleosome fragility is in large part DNA-encoded and that it poises genes for future context-specific activation in response to environmental stress and developmental cues.
核小体在所有真核生物以DNA为模板的过程中具有结构和调节功能。核小体在DNA上的位置以及潜在的组蛋白-DNA相互作用的稳定性会影响调节蛋白与DNA的结合。稳定性和位置都通过DNA序列、组蛋白翻译后修饰、组蛋白变体、染色质重塑因子和转录因子来调节。在这里，我们探讨了秀丽隐杆线虫胚胎中核小体特性对基因表达和发育的功能影响。我们进行了微球菌核酸酶（MNase）消化的时间进程实验，并测量了全基因组中核小体的相对敏感性或抗性。脆弱核小体由在MNase消化早期时间点优先回收的核小体DNA片段定义。核小体脆弱性与潜在DNA序列的AT含量呈强正相关。启动子核小体脆弱性与组蛋白修饰或组蛋白变体水平之间没有相关性。启动子中具有脆弱核小体的基因往往低水平表达，并以特定于上下文的方式表达，在神经元反应、免疫系统和应激反应中发挥作用。除了DNA编码的核小体脆弱性外，我们还在预期会发现不稳定核小体的位置发现了脆弱核小体，例如，在核小体与DNA结合因子竞争的转录因子结合位点。我们的数据表明，在秀丽隐杆线虫启动子中，核小体脆弱性在很大程度上是由DNA编码的，并且它使基因做好准备，以便在未来响应环境压力和发育线索时进行特定于上下文的激活。
