Cell‐type‐specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1^S858R Schinzel Giedion Syndrome mice

Abstract

Schinzel Giedion Syndrome (SGS) is an ultra‐rare autosomal dominant Mendelian disease presenting with abnormalities spanning multiple organ systems. The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug‐resistant seizures. SGS is caused by spontaneous variants in SETBP1, which encodes for the epigenetic hub SETBP1 transcription factor (TF). SETBP1 variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation and resulting in toxic accumulation, while those located outside cause milder atypical SGS. Due to the multisystem phenotype, we evaluated gene expression and regulatory programs altered in atypical SGS by snRNA‐seq of the cerebral cortex and kidney of Setbp1S858R heterozygous mice (corresponds to the human likely pathogenic SETBP1S867R variant) compared to matched wild‐type mice by constructing cell‐type‐specific regulatory networks. Setbp1 was differentially expressed in excitatory neurons, but known SETBP1 targets were differentially expressed and regulated in many cell types. Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney. Our results indicate SETBP1's role as an epigenetic hub leads to cell‐type‐specific differences in TF activity, gene targeting, and regulatory rewiring. This research provides a framework for investigating cell‐type‐specific variant impact on gene expression and regulation.

The landscape of SETBP1 gene expression and transcription factor activity across human tissues

“…Further, we examined the gene expression of 209 known SETBP1 targets we previously compiled [ 11 ] from SETBP1 ChIP-seq binding sites [ 28 ], MSigDB [ 29 ], SIGNOR [ 30 ], TRRUST [ 31 ], Piazza et al [ 2 ], and Antonyan et al [ 10 ]. We found that most known SETBP1 targets were also broadly expressed across adult human tissues (62.2% of known SETBP1 targets had a TPM>3 in >90% of tissues; Fig 3 ).…”

“…Furthermore, prior research showed that oncogenic apoptosis resistance and unresolved DNA damage signatures persist due to SETBP1 variants in SGS [ 11 , 37 ]. Here, we found that in non-diseased adult tissue, TCF4, a known apoptosis regulator [ 38 , 39 ], and APEX1, part of the SET complex in DNA damage response [ 10 ], also had variable TF activity across SGS-affected tissues.…”

“…Therefore, further research could utilize single-cell transcriptomics data or cell expression atlases to explore the cell-type-specific expression and functional variation of SETBP1 across cell types within a tissue. However, as we recently reported, SETBP1’s role as an epigenetic hub leads to cell-type-specific differences in TF activity, gene targeting, and regulatory rewiring in the mouse cerebral cortex and kidney [ 11 ]. This underscores the importance of future studies that generate and analyze the necessary data to understand cell-type-specific gene expression and TF activity across human tissues.…”

“…We used the SETBP1 target gene set compiled in Whitlock et al 2023 to obtain a list of known TF targets of SETBP1 [ 11 ]. We converted a list of human HGNC to human Ensembl IDs using gprofiler2 [ 20 ] (v.0.2.1), resulting in a final list of 209 genes.…”

Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq

“…To overcome the data sparsity in snRNA-seq [49], we pseudo-bulked both of our datasets and generated celltype-specific count matrices, as previously described [50]. We converted raw data from the Seurat object counts slot into Single Cell Experiment objects using SingleCellExperiment [47] v1.16.0 while also incorporating necessary metadata with information on sample origin (sample_id), condition (group_id), and cell type (cluster_id).…”