Cell-specific and shared regulatory elements control a multi-gene locus active in mammary and salivary glands [RNA-Seq]

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. Five genes (Csn1s1, Csn2, Csn1s2a, Csn1s2b, Csn3) are expressed in mammary glands and account for 50% of mRNAs during lactation, two (Prr27, Fdcsp) are salivary-specific and one (Odam) has dual specificity. We probed the function of 12 candidate control elements, individually and in combination, in the mouse genome. The super-enhancer is essential for the expression of Csn3, 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 facilitated the 10,000-fold activation of Csn2 during pregnancy. Our work identifies regulatory complexity of a multigene locus with an ancestral super-enhancer active in mammary and salivary tissue and local enhancers and promoter elements.调控携带具有不同细胞特异性基因的高密度基因座，仍是一道未解的科学难题。本研究针对一个经由基因复制演化而来的基因座展开探究，该基因座包含8个基因与20个候选调控元件，其中包含1个超级增强子（super-enhancer）。其中5个基因（Csn1s1、Csn2、Csn1s2a、Csn1s2b、Csn3）在乳腺中表达，其转录本占泌乳期总mRNA的50%；2个基因（Prr27、Fdcsp）为唾液腺特异性表达，另有1个基因（Odam）兼具双重表达特异性。我们在小鼠基因组中分别独立或联合探究了12个候选调控元件的功能。该超级增强子对Csn3、Odam及Fdcsp的表达至关重要，但对Csn1s1、Csn2与Csn1s2a的表达则基本非必需。Csn3的激活还需要其自身的局部增强子。局部增强子与细胞因子应答启动子元件之间的协同作用，促成了妊娠期间Csn2的10000倍激活。本研究揭示了一个多基因基因座的调控复杂性：该基因座拥有一个在乳腺与唾液腺组织中发挥功能的祖先型超级增强子，同时配有局部增强子与启动子元件。