Fig 2: S858R pericytes and microglia and multiple kidney cell types exhibit altered cooperation and regulation in proposed cell cycle and DNA damage mechanisms in SGS: Visualization of changes in regulation and cooperation of cell types in S858R cerebral cortex and kidney. (A) Schematic of proposed increased DNA damage and increased cell cycle mechanisms in the context of SGS. (B) Classification of altered regulation and cooperation through a change in network scores between TF SETBP1 (yellow) and its target genes from the gene set (light grey) associated with the corresponding target protein and proposed mechanisms of altered neurodevelopment in SGS mediated through Apex1 or Trp53 (dark grey). Heatmap showing the sign change in regulation and cooperation between conditions in the cerebral cortex (C) and kidney (D). Dot plot showing the magnitude of regulatory (direction and size of triangle) and cooperativity (teal to brown) network scores in the cerebral cortex (E) and kidney (F).

Fig 3: Differential community analysis of SETBP1 communities reveals groups of cell types with more similar SETBP1 differential communities: Jaccard Similarity Index (JI) between all SETBP1 differential communities in (A) cerebral cortex and (B) kidney.

Fig 4: Schematic overview of our approach (A) We generated single‐nuclei RNA‐seq (snRNA‐seq) from male C57BL/6J (WT) and Setbp1 S858R cerebral cortex and kidney tissues. (B) We processed and aggregated our data across samples to create cell‐type‐specific count matrices. (C) Next, we assessed cell‐type‐specific expression for Setbp1 and genes SETBP1 is known to target. (D) With decoupleR, we measured cell‐type‐specific TF activity. (E) We acquired protein–protein interaction data (PPI; green) from STRING and Transcription Factor‐motif data (TF‐motif; yellow) from CIS‐BP enriched for SETBP1 targets. We then built cell‐type‐specific TF‐gene regulatory networks with the data we generated by using the message‐passing algorithm PANDA to identify regulatory relationships between TFs (circles), genes (rectangles), and proteins (triangles) for each S858R and WT cell type in both tissues and investigated differential communities using differential community detection with ALPACA, differential gene targeting, cooperativity analysis, and functional enrichment analysis.

Fig 5: Increased differential gene targeting in S858R cerebral cortex and kidney cells indicates increased gene regulation and altered cell‐type‐specific mechanisms associated with SGS: Dot plot of the normalized total differential gene targeting by (A) cerebral cortex and (B) kidney cell types (teal for increased gene targeting in S858R compared to WT and brown for decreased gene targeting in S858R compared to WT; dot size corresponds to gene number). Functional Enrichment Analysis (FEA) of differentially targeted SETBP1 gene set in (C) cerebral cortex and (D) kidney cell types.