Coordination of two enhancers drives expression of olfactory trace amine-associated receptors IV

Olfactory sensory neurons (OSNs) are functionally defined by their expression of a unique odorant receptor (OR). Mechanisms underlying singular OR expression are well studied, and involve a massive cross-chromosomal enhancer interaction network. Trace amine-associated receptors (TAARs) form a distinct family of olfactory receptors, and here we find that mechanisms regulating Taar gene choice display many unique features. The epigenetic signature of Taar genes in TAAR OSNs is different from that in OR OSNs. We further identify that two TAAR enhancers conserved across placental mammals are absolutely required for expression of the entire Taar gene repertoire. Deletion of either enhancer dramatically decreases the expression probabilities of different Taar genes, while deletion of both enhancers completely eliminates the TAAR OSN populations. In addition, both of the enhancers are sufficient to drive transgene expression in the partially overlapped TAAR OSNs. We also show that the TAAR enhancers operate in cis to regulate Taar gene expression. Our findings reveal a coordinated control of Taar gene choice in OSNs by two remote enhancers, and provide an excellent model to study molecular mechanisms underlying formation of an olfactory subsystem. Main olfactory epithelium (MOE) mRNA profiles of wild type (WT), TAAR enhancer 2 +/- (het) and TAAR enhancer 2 -/- (homo) mice嗅觉感觉神经元（Olfactory sensory neurons, OSNs）的功能定义为表达单一嗅觉受体（odorant receptor, OR）。单一OR基因表达的调控机制已得到充分研究，其涉及庞大的跨染色体增强子互作网络。痕量胺相关受体（Trace amine-associated receptors, TAARs）是一类独立的嗅觉受体家族，本研究发现调控Taar基因选择的机制具备诸多独特特征。TAAR阳性OSNs中Taar基因的表观遗传标记特征，与OR阳性OSNs存在显著差异。本研究进一步鉴定出两类在有胎盘哺乳动物中保守的TAAR增强子，它们对整套Taar基因的表达均不可或缺。单独删除任一增强子均会显著降低不同Taar基因的表达概率，而同时删除两个增强子则会完全清除TAAR阳性OSNs群体。此外，两类增强子均可单独介导转基因在部分重叠的TAAR阳性OSNs中表达。本研究同时证实，TAAR增强子通过顺式作用调控Taar基因的表达。本研究结果揭示了两类远端增强子协同调控OSNs中Taar基因选择的机制，并为研究嗅觉亚系统形成的分子机制提供了优质实验模型。本数据集包含野生型（wild type, WT）、TAAR增强子2杂合敲除（TAAR enhancer 2 +/-，het）及TAAR增强子2纯合敲除（TAAR enhancer 2 -/-，homo）小鼠的主嗅觉上皮（main olfactory epithelium, MOE）mRNA表达谱。