Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis-regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans. Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years.

中文翻译：

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组合转录因子特征定义了 HSN 血清素能神经元调节景观

细胞分化由单个转录因子 (TF) 控制，这些转录因子共同激活特定细胞类型中的一系列增强子。这些 TF 组合如何识别和激活它们的目标序列仍然知之甚少。在这里，我们确定了控制秀丽隐杆线虫中血清素能 HSN 神经元分化的顺式调节转录代码。HSN 转录组的激活由六个 TF 的集合直接协调。该 TF 集合的结合位点簇形成了足以从头识别 HSN 神经元功能增强子的监管特征。在秀丽隐杆线虫神经元中，HSN 转录组与小鼠血清素神经元的转录组最相似。HSN TF 集体的小鼠直向同源物也调节血清素能分化，并且可以在功能上替代它们的蠕虫对应物，这表明存在深层同源性。我们的结果确定了控制相隔超过 7 亿年的两个物种中极其重要的神经元类型的监管格局的规则。