Biology subjects

Abel, T. R.

Publications and source records attributed to Abel, T. R..

3 recordsLinked to original sources

bioRxiv2025

Trem2*R47H and reduced TREM2 expression both mimic human Alzheimer's disease signatures in mice

INTRODUCTIONTREM2 loss of function variants are associated with late-onset Alzheimers disease (LOAD). We molecularly assessed mice with the missense variant, R47H (Trem2*R47HHSS), and mice with additional cryptic splicing and reduced Trem2 expression (Trem2*R47H) while comparing relevance to human LOAD. METHODSThe aberrant splice acceptor site in the Trem2*R47H mouse was humanized resulting in the Trem2*R47H humanized splice site (Trem2*R47HHSS) mouse. RNA sequencing was performed on mouse brain tissue and signatures were compared to human postmortem brain expression in LOAD cohorts. RESULTSTrem2*R47H mice had alternative splicing leading to reduced Trem2 expression; Trem2*R47HHSS mice expressed Trem2 at wild-type transcript and protein levels. Both models correlated with similar LOAD-associated signatures, and had similar effects on immune response, synapse, and vasculature biodomains. The Trem2*R47H model additionally affected extracellular matrix and myelination signatures. DISCUSSIONWe demonstrated that Trem2*R47H and Trem2*R47HHSS mice are complementary models for the study of molecular contributions to LOAD pathology.

neuroscience↗

bioRxiv2024

RUNX1 is Expressed in a Subpopulation of Dermal Fibroblasts and Higher RUNX1 Levels are Associated with the Severity of Systemic Sclerosis

The activation of Runt-related transcription factor 1 (RUNX1) in fibroblasts has been implicated in wound healing and fibrosis; however, the role of RUNX1 in the fibrotic progression of the autoimmune disease systemic sclerosis (SSc) is not known. Through gene expression analysis, we have demonstrated an association between the severity of dermal fibrosis and the expression levels of RUNX1 in the skin of patients with SSc. Additionally, we identified hypomethylated CpG sites proximal to the RUNX1 gene, implicating their potential role in the increased expression of RUNX1. Analysis of single-cell RNA-seq data from skin biopsies of individuals with SSc revealed that RUNX1 is higher in subpopulations of fibroblasts enriched in SSc, which are believed to contribute to fibrosis. Lastly, modulation of RUNX1 activity using an inhibitor caused a reduction in fibroblast contraction and proliferation rates. Altogether, this study is the first to demonstrate a potential role for RUNX1 in the pathogenesis of systemic sclerosis dermal fibrosis.

genomics↗

bioRxiv2024

Single-cell epigenomic dysregulation of Systemic Sclerosis fibroblasts via CREB1/EGR1 axis in self-assembled human skin equivalents

Systemic sclerosis (SSc) is an autoimmune disease characterized by skin fibrosis, internal organ involvement and vascular dropout. We previously developed and phenotypically characterized an in vitro 3D skin-like tissue model of SSc, and now analyze the transcriptomic (scRNA-seq) and epigenetic (scATAC-seq) characteristics of this model at single-cell resolution. SSc 3D skin-like tissues were fabricated using autologous fibroblasts, macrophages, and plasma from SSc patients or healthy control (HC) donors. SSc tissues displayed increased dermal thickness and contractility, as well as increased -SMA staining. Single-cell transcriptomic and epigenomic analyses identified keratinocytes, macrophages, and five populations of fibroblasts (labeled FB1 - 5). Notably, FB1 APOE-expressing fibroblasts were 12-fold enriched in SSc tissues and were characterized by high EGR1 motif accessibility. Pseudotime analysis suggests that FB1 fibroblasts differentiate from a TGF-{beta}1-responsive fibroblast population and ligand-receptor analysis indicates that the FB1 fibroblasts are active in macrophage crosstalk via soluble ligands including FGF2 and APP. These findings provide characterization of the 3D skin-like model at single cell resolution and establish that it recapitulates subsets of fibroblasts and macrophage phenotypes observed in skin biopsies.

genomics↗