Regulation of high-density loci harboring genes with different cell-specificities remains a puzzle. Here we investigate a locus that evolved through gene duplication and contains eight genes and 20 candidate regulatory elements, including one super-enhancer. Casein genes (Csn1s1, Csn2, Csn1s2a, Csn1s2b, Csn3) are expressed in mammary glands, induced 10,000-fold during pregnancy and account for 50% of mRNAs during lactation, Prr27 and Fdcsp are salivary-specific and Odam has dual specificity. We probed the function of 12 candidate regulatory elements, individually and in combination, in the mouse genome. The super-enhancer is essential for the expression of Csn3, Csn1s2b, Odam and Fdcsp but largely dispensable for Csn1s1, Csn2 and Csn1s2a. Csn3 activation also requires its own local enhancer. Synergism between local enhancers and cytokine-responsive promoter elements facilitates activation of Csn2 during pregnancy. Our work identifies the regulatory complexity of a multigene locus with an ancestral super-enhancer active in mammary and salivary tissue and local enhancers and promoter elements unique to mammary tissue.

对含有不同细胞特异性基因的高密度基因座的调控仍然是一个谜。在这里，我们研究了一个通过基因复制进化的基因座，包含 8 个基因和 20 个候选调控元件，其中包括一个超级增强子。酪蛋白基因（Csn1s1、Csn2、Csn1s2a、Csn1s2b、Csn3）在乳腺中表达，在怀孕期间诱导 10,000 倍，并在哺乳期间占 mRNA 的 50%，Prr27和Fdcsp具有唾液特异性，Odam具有双重特异性。我们单独或组合地探讨了小鼠基因组中 12 个候选调控元件的功能。超级增强子对于Csn3、  Csn1s2b、Odam和Fdcsp的表达至关重要，但对于Csn1s1、Csn2和Csn1s2a的表达基本上是可有可无的。Csn3的激活也需要它自己的局部增强子。局部增强子和细胞因子响应启动子元件之间的协同作用促进妊娠期间Csn2的激活。我们的工作确定了多基因位点的调控复杂性，该位点具有在乳腺和唾液组织中活跃的祖先超级增强子以及乳腺组织特有的局部增强子和启动子元件。