Department of Cellular and Molecular Immunology, Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.
Mol Cell. 2012 May 25;46(4):408-23. doi: 10.1016/j.molcel.2012.05.011.
Cell-type-specific control of gene expression is critical for the development of multicellular organisms. To investigate the mechanisms which underlie this, we have studied the regulation of the model genes Mdc and Il12b, whose stimulus-induced expression is tightly restricted to specific cells of the immune system. Surprisingly, we find that neither the promoter nor the enhancer sequences of these genes are sufficient to direct this cell-type specificity. Instead, the activities of upstream enhancers are repressed in nonexpressing cells by high levels of trimethylated H3K9 in their flanking regions. Genome-wide analysis indicates that this manner of regulation is shared by numerous enhancers of cell-type-specific genes. In dendritic cells and macrophages, the stimulus-induced demethylase Jmjd2d controls H3K9me3 levels at these regions, and is thereby required for Mdc and Il12b transcription. By experimentally assaying multiple enhancers in a variety of cell types, we show that regulation by H3K9me3 is a widely used mechanism which imparts specificity to the activities of otherwise broadly functional enhancers.
细胞类型特异性基因表达的调控对于多细胞生物的发育至关重要。为了研究其背后的机制，我们研究了模型基因 Mdc 和 Il12b 的调控，它们的诱导表达严格局限于免疫系统的特定细胞。令人惊讶的是，我们发现这些基因的启动子或增强子序列都不足以指导这种细胞类型特异性。相反，上游增强子的活性在非表达细胞中被其侧翼区域中高甲基化的 H3K9 所抑制。全基因组分析表明，这种调控方式被许多细胞类型特异性基因的增强子共享。在树突状细胞和巨噬细胞中，诱导型去甲基酶 Jmjd2d 控制这些区域的 H3K9me3 水平，因此对于 Mdc 和 Il12b 的转录是必需的。通过在多种细胞类型中实验性地检测多个增强子，我们表明 H3K9me3 的调控是一种广泛使用的机制，它赋予了原本广泛功能的增强子特异性。
