Therapeutic targeting of epigenetic modulators offers a novel approach to the treatment of multiple diseases. The cellular consequences of chemical compounds that target epigenetic regulators (epi-drugs) are complex. Epi-drugs affect global cellular phenotypes and cause local changes to gene expression due to alteration of a gene chromatin environment. Despite increasing use in the clinic, the mechanisms responsible for cellular changes are unclear. Specifically, to what degree the effects are a result of cell-wide changes or disease related locus specific effects is unknown. Here we developed a platform to systematically and simultaneously investigate the sensitivity of epi-drugs at hundreds of genomic locations by combining DNA barcoding, unique split-pool encoding, and single cell expression measurements. Internal controls are used to isolate locus specific effects separately from any global consequences these drugs have. Using this platform we discovered wide-spread loci specific sensitivities to epi-drugs for three distinct epi-drugs that target histone deacetylase, DNA methylation and bromodomain proteins. By leveraging ENCODE data on chromatin modification, we identified features of chromatin environments that are most likely to be affected by epi-drugs. The measurements of loci specific epi-drugs sensitivities will pave the way to the development of targeted therapy for personalized medicine.

中文翻译：

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位点特异性表观遗传药物敏感性。


表观遗传调节剂的治疗靶向为治疗多种疾病提供了一种新方法。针对表观遗传调节剂（表观药物）的化合物对细胞的影响是复杂的。 Epi-药物影响整体细胞表型，并由于基因染色质环境的改变而引起基因表达的局部变化。尽管在临床上的使用越来越多，但导致细胞变化的机制尚不清楚。具体而言，这些影响在多大程度上是细胞范围变化或疾病相关位点特异性影响的结果尚不清楚。在这里，我们开发了一个平台，通过结合 DNA 条形码、独特的分割池编码和单细胞表达测量，系统地、同时地研究数百个基因组位置的表观药物的敏感性。内部控制用于将位点特异性效应与这些药物产生的任何全球后果分开。利用这个平台，我们发现了针对组蛋白脱乙酰酶、DNA 甲基化和溴结构域蛋白的三种不同表观药物对表观药物的广泛位点特异性敏感性。通过利用染色质修饰的 ENCODE 数据，我们确定了最有可能受到表观药物影响的染色质环境的特征。位点特异性表观药物敏感性的测量将为个性化医疗的靶向治疗的发展铺平道路。