Biology subjects

Thompson, S. D.

Publications and source records attributed to Thompson, S. D..

3 recordsLinked to original sources

bioRxiv2026

Single-cell transcriptional landscape of muscle-derived stem/progenitor cells reveals hallmarks of aging and rejuvenation

Muscle-derived stem/progenitor cells (MDSPCs) are an adult stem cell population with demonstrated regenerative and rejuvenative potential distinct from other muscle progenitor cells. However, their molecular identity and developmental status remain poorly defined. Using single-cell transcriptomics and proteomics, we comprehensively profiled murine MDSPCs across age groups. We show that MDSPCs exist along a transcriptional continuum of maturation--ranging from metabolically active, proliferative early-stage cells to late-stage, lineage-committed myogenic populations. While lacking canonical pluripotency markers, early-stage MDSPCs express gene programs associated with embryonic progenitor identity, suggesting a non-canonical, multipotent-like state. These features distinguish them from both satellite cells and committed myoblasts. Aging reshapes this continuum by reducing stemness-associated signatures while enhancing differentiation programs and oxidative stress. Our identification of distinct MDSPC states provide critical insights into mechanisms that underly tissue regeneration and aging. These findings offer a blueprint for development of future regenerative therapies to combat age-related functional decline.

cell biology↗

bioRxiv2024

Using Functional Genomic Data in Monocytes/Macrophages and Genotyping to Nominate Disease-Driving Single Nucleotide Polymorphisms and Target Genes in Juvenile Idiopathic Arthritis

IntroductionGWAS have identified multiple regions that confer risk for juvenile idiopathic arthritis (JIA). However, identifying the single nucleotide polymorphisms (SNPs) that drive disease risk is impeded by the SNPs that identify risk loci being in linkage disequilibrium (LD) with hundreds of other SNPs. Since the causal SNPs remain unknown, it is difficult to identify target genes and use genetic information to inform patient care. We used genotyping and functional data in primary human monocytes/macrophages to nominate disease-driving SNPs on JIA risk haplotypes and identify their likely target genes. MethodsWe identified JIA risk haplotypes using Immunochip data from Hinks et al (Nature Gen 2013) and the meta-analysis from McIntosh et al (Arthritis Rheum 2017). We used genotyping data from 3,939 children with JIA and 14,412 healthy controls to identify SNPs that: (1) were situated within open chromatin in multiple immune cell types and (2) were more common in children with JIA than the controls (p< 0.05). We intersected the chosen SNPs (n=846) with regions of bi-directional transcription initiation characteristic of non-coding regulatory regions detected using dREG to analyze GRO-seq data. Finally, we used MicroC data to identify gene promoters interacting with the regulatory regions harboring the candidate causal SNPs. ResultsWe identified 190 SNPs that overlap with dREG peaks in monocytes and126 SNPs that overlap with dREG peaks in macrophages. Of these SNPs, 101 were situated within dREG peaks in both monocytes and macrophages, suggesting that these SNPs exert their effects independent of the cellular activation state. MicroC data in monocytes identified 20 genes/transcripts whose promoters interact with the enhancers harboring the SNPs of interest. ConclusionSNPs in JIA risk regions that are candidate causal variants can be further screened using functional data such as GRO-seq. This process identifies a finite number of candidate causal SNPs, the majority of which are likely to exert their biological effects independent of cellular activation state in monocytes. Three-dimensional chromatin data generated with MicroC identifies genes likely to be influenced by these SNPs. These studies demonstrate the importance of investigations into the role of innate immunity in JIA.

genetics↗

bioRxiv2023

A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

Single nucleotide polymorphisms (SNP) near the ERAP2 gene are associated with autoimmune conditions such as Crohns disease, and birdshot chorioretinopathy, as well as protection against lethal infections, including the Black Death. Due to high linkage disequilibrium (LD), a great number of trait-associated SNPs are correlated with ERAP2 expression, however their functional mechanisms remain unidentified. We used genome editing and functional genomics to identify causal variants that remain obscured by LD. We demonstrate by reciprocal allelic replacement that ERAP2 expression is directly controlled by the genotype of splice region SNP rs2248374. However, we demonstrate that autoimmune disease-risk SNPs located near the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the LNPEP promoter region and the ERAP2 promoter and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the disease-associated SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that clustered GWAS signals associated with diverse autoimmune conditions and lethal infections act in concert to control ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.

genomics↗