Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA.
Transgenic Core, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland, 20892, USA.
Nat Commun. 2023 Aug 17;14(1):4992. doi: 10.1038/s41467-023-40712-0.
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.
调控高浓度基因座的活性一直是个谜，这些基因座上的基因具有不同的细胞特异性。在这里，我们研究了一个通过基因复制进化而来的基因座，该基因座包含 8 个基因和 20 个候选调控元件，其中包括一个超级增强子。乳蛋白基因（Csn1s1、Csn2、Csn1s2a、Csn1s2b、Csn3）在乳腺中表达，在怀孕期间诱导 10000 倍，在哺乳期占 50%的 mRNA，Prr27 和 Fdcsp 是唾液特异性的，Odam 具有双重特异性。我们在小鼠基因组中单独和组合探测了 12 个候选调控元件的功能。超级增强子对 Csn3、Csn1s2b、Odam 和 Fdcsp 的表达是必需的，但对 Csn1s1、Csn2 和 Csn1s2a 的表达则在很大程度上是可有可无的。Csn3 的激活也需要其自身的局部增强子。局部增强子和细胞因子反应启动子元件之间的协同作用促进了 Csn2 在怀孕期间的激活。我们的工作确定了一个多基因座的调控复杂性，该基因座具有一个祖先超级增强子，在乳腺和唾液组织中具有活性，并且在乳腺组织中具有独特的局部增强子和启动子元件。
