Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypicalSetbp1^S858RSchinzel 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 resulting in toxic accumulation, while those located outside cause milder atypical SGS. Due to the multi-system phenotype, we evaluated gene expression and regulatory programs altered in atypical SGS by snRNA-seq of 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 the role of SETBP1 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 ofSETBP1gene expression and transcription factor activity across human tissues

“…5 ). Likewise, we and others (Banfi et al, 2021; Antonyan & Ernst, 2022; Whitlock et al, 2023) have hypothesized that in the presence of pathogenic germline variants, alterations in TCF4 or APEX1 activity lead to apoptosis resistance or increased DNA damage in SGS. Our results suggest both exhibit activator roles across many tissues in non-diseased adult tissues, so disease-associated perturbations may impact SETBP1 TF activity, contributing to SGS.…”

“…Additionally, as we conducted the analyses here in bulk profiles, we cannot assess the gene expression and TF activity of particular cell types. 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 (Whitlock et al, 2023). 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.…”

“…Further, we examined the gene expression of 209 known SETBP1 targets we previously compiled (Whitlock et al, 2023) from SETBP1 ChIP-seq binding sites (Kolmykov et al, 2021), MSigDB (Liberzon et al, 2015), SIGNOR (Lo Surdo et al, 2023), TRRUST (Han et al, 2018), Piazza et al (Piazza et al, 2018), and Antonyan et al (Antonyan & Ernst, 2022). 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.…”

“…Furthermore, prior research showed that oncogenic apoptosis resistance and unresolved DNA damage signatures persist due to SETBP1 variants in SGS (Banfi et al, 2021; Whitlock et al, 2023). Here, we found that in non-diseased adult tissue, TCF4, a known apoptosis regulator (Xie et al, 2012; Forrest et al, 2013), and APEX1, part of the SET complex in DNA damage response (Antonyan & Ernst, 2022), also had variable TF activity across SGS-affected tissues.…”

“…We used the SETBP1 target gene set compiled in Whitlock et al 2023 to obtain a list of known TF targets of SETBP1 (Whitlock et al, 2023). We converted a list of human HGNC to human Ensembl IDs using gprofiler2 (Kolberg et al, 2020) (v.0.2.1), resulting in a final list of 209 genes.…”