The majority of the human genome does not encode proteins. Many of these noncoding regions contain important regulatory sequences that control gene expression. To date, most studies have focused on activators such as enhancers, but regions that repress gene expression-silencers-have not been systematically studied. We have developed a system that identifies silencer regions in a genome-wide fashion on the basis of silencer-mediated transcriptional repression of caspase 9. We found that silencers are widely distributed and may function in a tissue-specific fashion. These silencers harbor unique epigenetic signatures and are associated with specific transcription factors. Silencers also act at multiple genes, and at the level of chromosomal domains and long-range interactions. Deletion of silencer regions linked to the drug transporter genes ABCC2 and ABCG2 caused chemo-resistance. Overall, our study demonstrates that tissue-specific silencing is widespread throughout the human genome and probably contributes substantially to the regulation of gene expression and human biology.

中文翻译：

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系统识别人体细胞中的消音器。

大多数人类基因组不编码蛋白质。许多这些非编码区包含控制基因表达的重要调控序列。迄今为止，大多数研究都集中在增强子等激活剂上，但抑制基因表达的区域——沉默子——尚未得到系统研究。我们开发了一个系统，该系统基于消音器介导的半胱天冬酶 9 转录抑制，以全基因组方式识别消音器区域。我们发现消音器分布广泛，并且可能以组织特异性方式起作用。这些消音器具有独特的表观遗传特征，并与特定的转录因子相关。消音器也作用于多个基因，在染色体结构域和长程相互作用的水平上。与药物转运蛋白基因 ABCC2 和 ABCG2 相关的沉默区域的缺失导致了化学抗性。总体而言，我们的研究表明，组织特异性沉默在整个人类基因组中普遍存在，并且可能对基因表达和人类生物学的调节有重大贡献。