The Role of Tissue- and Cell-type-specific Expression and Regulation in SETBP1-associated Diseases

Authors

Jordan Hailey Whitlock, University of Alabama at Birmingham

Advisory Committee Chair

Brittany N Lasseigne

Advisory Committee Members

James F Collawn

Constanza J Cortes

James F George

Haosheng Sun

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

SET binding protein 1 (SETBP1) encodes a transcription factor (TF) participating in diverse cellular processes. SETBP1 is an epigenetic hub associated with variants linked to three distinct diseases. Germline variants cause rare pediatric Schinzel Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disorder (SETBP1-HD), featuring multisystemic abnormalities and neurodegeneration or milder brain issues with hypotonia, respectively. On the other hand, somatic variants contribute to hematological malignancies and adult cancer. To understand tissue-specific SETBP1 mechanisms, public RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project were analyzed. SETBP1 and targets were broadly expressed across 31 adult human tissues, revealing three distinct expression patterns: transcription regulation, DNA binding, and mitochondrial function. Tissue-specific TF activity of SETBP1 and targets demonstrated context-driven regulation. Alongside tissue-specific signatures, we developed a Shiny app, facilitating the exploration of TF activity across 758 TFs in human tissues. Previous studies have shown the underlying cellular heterogeneity is masked in bulk approaches. Out of the three-associated diseases, we focused on SGS and looked at the influence of a variant on expression and regulation in a cell-type-specific manner. To investigate the cell-type-specific regulation and expression underlying atypical SGS, we performed single-nucleus RNA sequencing (snRNA-seq) of cerebral cortex and kidney tissues in Setbp1S858R heterozygous mice (corresponding to human pathogenic variant SETBP1S867R) and constructed cell-type-specific regulatory networks. Our analysis revealed differential expression of Setbp1 in excitatory neurons and diverse regulation of SETBP1 targets across atypical SGS cell types. In addition, we found molecular drivers of classical SGS also persist post-birth and perpetuate in additional unstudied affected tissues of atypical SGS. This research establishes a framework to investigate variant impact in SETBP1 that leads to cell-type-specific variations in TF activity, gene targeting, and regulatory rewiring.

Recommended Citation

Whitlock, Jordan Hailey, "The Role of Tissue- and Cell-type-specific Expression and Regulation in SETBP1-associated Diseases" (2023). All ETDs from UAB. 3541.
https://digitalcommons.library.uab.edu/etd-collection/3541