Fig. 3: Cells lacking KAT3 proteins do not die or dedifferentiate, but acquire a novel, molecularly undefined fate.

a Violin plots show the change in expression of gene sets associated with stemness¹⁹ and different neuronal differentiation stages²⁰ during development (purple bar) or with different cell types in the adult mouse cortex¹⁸ (green bar). Each dot represents a single gene. Number of genes tested per cell type: stem cell = 195, neural stem cell = 365, neuroprogenitor = 200, neuroblast = 109, immature neuron = 353, CA1_pyr mature = 371, S1_pyr mature = 251, interneuron = 337, endothelial = 337, mural = 141, ependymal = 420, microglia = 387, astrocyte = 223, oligodendrocyte = 418. Bar sizes are proportional to the percentage of up- or downregulated genes in each gene set as indicated by the number in each bar. Bar colors indicate the significance of the enrichment (−log10) in a hypergeometric test for the number of regulated genes. Enrichments with p-values < 5e–10 are labeled with an asterisk (p-val_{Inmature_neuron} = 4.82e–17; p-val_{CA1_Pyramidal} = 2.59e–101; p-val_{S1_Pyramidal} = 4.69e–25; p-val_Microglia = 3.49e–15). b Scheme of the single-nucleus RNA-seq experiment. c UMAP plot of integrated analysis of snRNA-seq datasets from the dorsal hippocampus of dKAT3-fKOs and control littermates. d UMAP plots showing identified populations in the hippocampus of control littermates (left) and dKAT3-ifKO mice 2 (center) and 4 (right) weeks after TMX treatment. Nuclei are colored by their classification label as indicated. e Boxplots showing the expression of the top 20 markers for the 10 cell types detected in the hippocampus of control mice and the two new clusters detected in dKAT3-ifKO mice 1 month after TMX (Supplementary Data 2). Whiskers lengths are 1.5 the interquartile range from the box. Abbreviations: Pyr, pyramidal; Oligodendr, oligodendrocyte. f, g Single-nucleus trajectory analysis of hippocampal excitatory neurons reveals cell state-transitions toward a non-functional interstate deadlock. Nuclei are colored by experimental condition (f) or cluster subpopulation (g) as indicated in the legends. Loss of dKAT3s caused the progressive relocation of the cells from the root in the branches A, B, and C (expressing markers for different types of excitatory neurons) towards the outcome in branches D and E that are populated by the type of cells described in (e) that do not express distinctive markers. Source data for graphs in panels (a) and (e) are provided as a Source data file.