Runx3 and Brn3a interplay orchestrates the transcriptional program in the early stages of proprioceptive neuron development

Abstract The development and diversification of proprioceptive neurons, which reside in the dorsal root ganglia (DRG) and express the tropomyosin receptor kinase C (TrkC), depend on the transcription factor (TF) Runx3. As one of the major functions of TrkC neurons is to coordinate limb movements, Runx3-deficient mice develop severe limb ataxia due to TrkC neuron cell death. In TrkC neurons Runx3 expression is driven by the gene proximal P2 promoter. Accordingly, P2-/- mice develop severe ataxia. Heterozygous (P2+/-) vs. homozygous (P2-/-) TrkC neuron transcriptome highlighted a repertoire of differentially expressed genes (DEG). The Intersection of Runx3 genomic occupancy-associated genes and DEG data discovered 244 high-confidence Runx3 target genes (HCT). We also analyzed the genomic occupancy of two additional TFs, Brn3a and Isl1, that play a role in sensory neuron development and determined the landscape of histone H3 acetylated lysine 27 (H3K27Ac) and transpoase-accessible chromatin with sequencing (ATAC-seq)-marked chromatin regions in E11.5 TrkC neurons. These analyses shed new light on the interplay of Runx3, Brn3a, Isl1, and open chromatin regions in regulating the HCT genes in the early developmental stages of TrkC neurons.