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

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 cluster +/- (het) and TAAR cluster -/- (homo) mice嗅觉感觉神经元（Olfactory sensory neurons, OSNs）的功能定义为表达唯一的气味受体（odorant receptor, OR）。目前针对单个OR基因选择性表达的分子机制已有充分研究，其涉及大规模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基因的表观遗传修饰特征与OR阳性OSNs存在显著差异。本研究进一步鉴定出两个在胎盘哺乳动物中保守的TAAR增强子，二者对整套Taar基因的表达是绝对必需的：单独删除任一增强子会显著降低不同Taar基因的表达概率，而同时删除两个增强子则会完全消除TAAR阳性OSN群体。此外，两个增强子均可在部分重叠的TAAR阳性OSNs中驱动转基因表达。研究还证实，TAAR增强子以顺式作用方式调控Taar基因的表达。本研究揭示了两个远端增强子协同调控OSNs中Taar基因选择的分子机制，为研究嗅觉亚系统形成的分子机理提供了优秀模型。本数据集包含野生型（wild type, WT）、TAAR基因簇杂合敲除（TAAR cluster +/-，het）及纯合敲除（TAAR cluster -/-，homo）小鼠的主嗅觉上皮（main olfactory epithelium, MOE）mRNA转录谱。