Epigenetic editing is an emerging technology that uses artificial transcription factors (aTFs) to regulate expression of a target gene. Although human genes can be robustly upregulated by targeting aTFs to promoters, the activation induced by directing aTFs to distal transcriptional enhancers is substantially less robust and consistent. Here we show that long-range activation using CRISPR-based aTFs in human cells can be made more efficient and reliable by concurrently targeting an aTF to the target gene promoter. We used this strategy to direct target gene choice for enhancers capable of regulating more than one promoter and to achieve allele-selective activation of human genes by targeting aTFs to single-nucleotide polymorphisms embedded in distally located sequences. Our results broaden the potential applications of the epigenetic editing toolbox for research and therapeutics.

表观遗传编辑是一种新兴技术，它使用人工转录因子 (aTF) 来调节靶基因的表达。虽然人类基因可以通过将 aTFs 靶向启动子来强烈上调，但通过将 aTFs 引导至远端转录增强子诱导的激活显着不那么稳健和一致。在这里，我们展示了在人类细胞中使用基于 CRISPR 的 aTF 的远程激活可以通过同时将 aTF 靶向靶基因启动子来提高效率和可靠性。我们使用这种策略来指导能够调节多个启动子的增强子的靶基因选择，并通过将 aTF 靶向嵌入远端序列中的单核苷酸多态性来实现人类基因的等位基因选择性激活。