Control of neuronal terminal differentiation through cell context-dependent CFI-1/ARID3 functions

ARID3 transcription factors are expressed in the nervous system, but their functions and mechanisms of action are largely unknown. Here, we generated in vivo a genome-wide binding map for CFI-1, the sole C. elegans ARID3 ortholog. We identified 6,396 protein-coding genes as putative direct targets of CFI-1, most of which (77%) are expressed in post-mitotic neurons and encode terminal differentiation markers (e.g., neurotransmitter receptors, ion channels, neuropeptides). To gain mechanistic insights, we focused on two neuron types. In sensory neurons (IL2 class), CFI-1 exerts a dual role: it acts directly to activate, and indirectly to repress, distinct terminal differentiation genes. In motor neurons, however, CFI-1 acts directly as a repressor, continuously antagonizing three transcriptional activators (UNC-3/Ebf, LIN-39/Hox4-5, MAB-5/Hox6-8). By focusing on a glutamate receptor gene (glr-4/GRIK1), we found CFI-1 exerts its repressive activity through proximal binding to the glr-4 locus. Further, the core DNA binding domain of CFI-1 is partially required for glr-4 repression in motor neurons. Altogether, this study uncovers cell context-dependent mechanisms through which a single ARID3 protein controls the terminal differentiation of distinct neuron types.