Tetrad Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell. 2013 Jul 18;154(2):325-36. doi: 10.1016/j.cell.2013.06.039.
The molecular mechanisms regulating olfactory receptor (OR) expression in the mammalian nose are not yet understood. Here, we identify the transient expression of histone demethylase LSD1 and the OR-dependent expression of adenylyl cyclase 3 (Adcy3) as requirements for initiation and stabilization of OR expression. As a transcriptional coactivator, LSD1 is necessary for desilencing and initiating OR transcription, but as a transcriptional corepressor, it is incompatible with maintenance of OR expression, and its downregulation is imperative for stable OR choice. Adcy3, a sensor of OR expression and a transmitter of an OR-elicited feedback, mediates the downregulation of LSD1 and promotes the differentiation of olfactory sensory neurons (OSNs). This novel, three-node signaling cascade locks the epigenetic state of the chosen OR, stabilizes its singular expression, and prevents the transcriptional activation of additional OR alleles for the life of the neuron.
调控哺乳动物鼻子中嗅觉受体（OR）表达的分子机制尚不清楚。在这里，我们发现组蛋白去甲基化酶 LSD1 的瞬时表达和腺苷酸环化酶 3（Adcy3）的 OR 依赖性表达是启动和稳定 OR 表达的要求。作为转录共激活因子，LSD1 对于去沉默和起始 OR 转录是必需的，但作为转录核心抑制因子，它与 OR 表达的维持不兼容，其下调对于 OR 选择的稳定是至关重要的。Adcy3 是 OR 表达的传感器和 OR 引发的反馈的传递者，介导 LSD1 的下调，并促进嗅觉感觉神经元（OSN）的分化。这个新的、三节点信号级联锁定了所选 OR 的表观遗传状态，稳定了其单一表达，并防止了神经元寿命内其他 OR 等位基因的转录激活。
