Chemical genomics reveals histone deacetylases are required for core regulatory transcription
Chemical genomics reveals histone deacetylases are required for core regulatory transcription
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DOI：
10.1038/s41467-019-11046-7
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发表时间：
2019-07-08
影响因子：
16.6
通讯作者：
Khan, Javed
中科院分区：
文献类型：
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作者：
Gryder, Berkley E.;Wu, Lei;Khan, Javed
身份决定转录因子（TF）或核心调控（CR）TF由细胞类型特异性超级增强子（SE）控制。选择性抑制CR回路的药物对于癌症治疗具有高度的意义。在腺泡状横纹肌肉瘤中，PAX 3-FOXO 1激活SE以诱导其他CR TF的表达，为研究癌细胞对CR转录的成瘾提供了模型系统。使用化学遗传学，化学物质的生物学结果的系统筛选，在这里，我们报告的表观遗传化学探针能够区分SE驱动的转录和组成型转录的屏幕上。我们发现，化学探针沿着乙酰化轴，而不是甲基化轴，选择性地破坏CR转录。此外，我们发现组蛋白脱乙酰酶（HDAC）是必不可少的CR TF转录。我们使用选择性抑制剂进一步剖析HDAC亚型的贡献，包括新开发的选择性HDAC 3抑制剂LW 3。我们表明HDAC 1/2/3是共同必需的同种型，当共同抑制时，停止CR转录，使CR TF位点超可及并破坏染色质循环。
Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.