Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA; Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA.
Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA; University of Chicago Neuroscience Institute, Chicago, IL 60637, USA.
Cell Rep. 2023 Mar 28;42(3):112220. doi: 10.1016/j.celrep.2023.112220. Epub 2023 Mar 9.
AT-rich interaction domain 3 (ARID3) transcription factors are expressed in the nervous system, but their mechanisms of action are largely unknown. Here, we provide, in vivo, a genome-wide binding map for CFI-1, the sole C. elegans ARID3 ortholog. We identify 6,396 protein-coding genes as putative direct targets of CFI-1, most of which encode neuronal terminal differentiation markers. In head sensory neurons, CFI-1 directly activates multiple terminal differentiation genes, thereby acting as a terminal selector. In motor neurons, however, CFI-1 acts as a direct repressor, continuously antagonizing three transcriptional activators. By focusing on the glr-4/GRIK4 glutamate receptor locus, we identify proximal CFI-1 binding sites and histone methyltransferase activity as necessary for glr-4 repression. Rescue assays reveal functional redundancy between core and extended DNA-binding ARID domains and a strict requirement for REKLES, the ARID3 oligomerization domain. Altogether, this study uncovers cell-context-dependent mechanisms through which a single ARID3 protein controls the terminal differentiation of distinct neuron types.
富含 AT 相互作用结构域 3（ARID3）的转录因子在神经系统中表达，但它们的作用机制在很大程度上尚不清楚。在这里，我们提供了线虫唯一的 ARID3 直系同源物 CFI-1 的体内全基因组结合图谱。我们确定了 6396 个编码蛋白的基因作为 CFI-1 的潜在直接靶标，其中大多数编码神经元终末分化标记物。在头部感觉神经元中，CFI-1 直接激活多个终末分化基因，从而充当终末选择器。然而，在运动神经元中，CFI-1 作为直接抑制剂，持续拮抗三个转录激活因子。通过关注 glr-4/GRIK4 谷氨酸受体基因座，我们确定了近端 CFI-1 结合位点和组蛋白甲基转移酶活性对于 glr-4 抑制是必需的。挽救实验揭示了核心和扩展 DNA 结合 ARID 结构域之间的功能冗余性，以及 ARID3 寡聚化结构域 REKLES 的严格要求。总之，这项研究揭示了单个 ARID3 蛋白通过依赖细胞上下文的机制来控制不同神经元类型的终末分化。
