Sorbonne Université, CNRS, Institut de Biologie Paris-Seine, Biological Adaptation and Ageing, B2A-IBPS, 75005, Paris, France.
Nucleic Acids Res. 2022 May 20;50(9):5095-5110. doi: 10.1093/nar/gkac346.
Promoters and enhancers are sites of transcription initiation (TSSs) and carry specific histone modifications, including H3K4me1, H3K4me3, and H3K27ac. Yet, the principles governing the boundaries of such regulatory elements are still poorly characterized. Alu elements are good candidates for a boundary function, being highly abundant in gene-rich regions, while essentially excluded from regulatory elements. Here, we show that the interval ranging from TSS to first upstream Alu, accommodates all H3K4me3 and most H3K27ac marks, while excluding DNA methylation. Remarkably, the average length of these intervals greatly varies in-between tissues, being longer in stem- and shorter in immune-cells. The very shortest TSS-to-first-Alu intervals were observed at promoters active in T-cells, particularly at immune genes, where first-Alus were traversed by RNA polymerase II transcription, while accumulating H3K4me1 signal. Finally, DNA methylation at first-Alus was found to evolve with age, regressing from young to middle-aged, then recovering later in life. Thus, the first-Alus upstream of TSSs appear as dynamic boundaries marking the transition from DNA methylation to active histone modifications at regulatory elements, while also participating in the recording of immune gene transcriptional events by positioning H3K4me1-modified nucleosomes.
启动子和增强子是转录起始位点（TSS）的所在地，携带特定的组蛋白修饰，包括 H3K4me1、H3K4me3 和 H3K27ac。然而，控制这些调节元件边界的原则仍未得到很好的描述。Alu 元件是边界功能的良好候选者，它们在基因丰富的区域中高度丰富，而基本上被排除在调节元件之外。在这里，我们表明，从 TSS 到第一个上游 Alu 的间隔，容纳了所有的 H3K4me3 和大多数的 H3K27ac 标记，而排除了 DNA 甲基化。值得注意的是，这些间隔的平均长度在组织之间有很大的差异，在干细胞中较长，在免疫细胞中较短。在 T 细胞中活跃的启动子中观察到的 TSS 到第一个 Alu 的最短间隔，特别是在免疫基因中，第一个 Alu 被 RNA 聚合酶 II 转录穿过，同时积累 H3K4me1 信号。最后，发现第一个 Alu 上的 DNA 甲基化随着年龄的增长而演变，从年轻到中年逐渐消退，然后在生命后期恢复。因此，TSS 上游的第一个 Alu 似乎是动态边界，标志着从 DNA 甲基化到调节元件中活跃的组蛋白修饰的转变，同时通过定位 H3K4me1 修饰的核小体参与记录免疫基因转录事件。
