Scruggs Benjamin S, Gilchrist Daniel A, Nechaev Sergei, Muse Ginger W, Burkholder Adam, Fargo David C, Adelman Karen
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Center for Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Mol Cell. 2015 Jun 18;58(6):1101-12. doi: 10.1016/j.molcel.2015.04.006. Epub 2015 May 28.
Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the regulation or function of anti-sense promoters and the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites (TSSs) near mouse mRNA genes. We find that coupled sense and anti-sense TSSs precisely define the boundaries of a nucleosome-depleted region (NDR) that is highly enriched in transcription factor (TF) motifs. Notably, as the distance between sense and anti-sense TSSs increases, so does the size of the NDR, the level of signal-dependent TF binding, and gene activation. We further discover a group of anti-sense TSSs in macrophages with an enhancer-like chromatin signature. Interestingly, this signature identifies divergent promoters that are activated during immune challenge. We propose that anti-sense promoters serve as platforms for TF binding and establishment of active chromatin to further regulate or enhance sense-strand mRNA expression.
起源于哺乳动物蛋白质编码基因上游的反义转录是一种有充分文献记载的现象，但对于反义启动子及其产生的非编码RNA的调控或功能却知之甚少。在这里，我们在核苷酸分辨率水平上定义了小鼠mRNA基因附近的双向转录起始位点（TSS）。我们发现，正向和反义TSS精确地界定了一个核小体缺失区域（NDR）的边界，该区域富含转录因子（TF）基序。值得注意的是，随着正向和反义TSS之间距离的增加，NDR的大小、信号依赖的TF结合水平以及基因激活程度也会增加。我们进一步在巨噬细胞中发现了一组具有增强子样染色质特征的反义TSS。有趣的是，这种特征识别出在免疫挑战期间被激活的双向启动子。我们提出，反义启动子作为TF结合和活性染色质建立的平台，以进一步调节或增强有义链mRNA的表达。
