Differential gene transcription enables development and homeostasis in all animals and is regulated by two major classes of distal cis-regulatory DNA elements (CREs): enhancers and silencers. Although enhancers have been thoroughly characterized, the properties and mechanisms of silencers remain largely unknown. By an unbiased genome-wide functional screen in Drosophila melanogaster S2 cells, we discover a class of silencers that bind one of three transcription factors (TFs) and are generally not included in chromatin-defined CRE catalogs as they mostly lack detectable DNA accessibility. The silencer-binding TF CG11247, which we term Saft, safeguards cell fate decisions in vivo and functions via a highly conserved domain we term zinc-finger-associated C-terminal (ZAC) and the corepressor G9a, independently of G9a’s H3K9-methyltransferase activity. Overall, our identification of silencers with unexpected properties and mechanisms has important implications for the understanding and future study of repressive CREs, as well as the functional annotation of animal genomes.

中文翻译：

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全基因组筛选可识别具有不同染色质特性和抑制机制的沉默剂


差异基因转录使所有动物都能发育和稳态，并受两大类远端顺式调节 DNA 元件 （CRE） 的调节：增强子和沉默子。尽管已经对增强子进行了彻底的表征，但消音器的特性和机制在很大程度上仍然未知。通过在黑腹果蝇 S2 细胞中进行无偏倚的全基因组功能筛选，我们发现了一类结合三种转录因子 （TF） 之一的沉默剂，并且通常不包括在染色质定义的 CRE 目录中，因为它们大多缺乏可检测的 DNA 可及性。沉默器结合的 TF CG11247，我们称之为 Saft，保护体内细胞命运的决定 ，并通过我们称为锌指相关 C 末端 （ZAC） 的高度保守结构域和辅阻遏物 G9a 发挥作用，独立于 G9a 的 H3K9-甲基转移酶活性。总体而言，我们鉴定出具有意想不到的特性和机制的沉默器，对于理解和未来研究抑制性 CREs 以及动物基因组的功能注释具有重要意义。