Biology subjects

Jones, E. F.

Publications and source records attributed to Jones, E. F..

5 recordsLinked to original sources

bioRxiv2026

Mitral regurgitation induces a unique fibroblast population associated with atrial fibrillation susceptibility

Background: Mitral regurgitation (MR) is a major risk factor for the development of atrial fibrillation (AF), yet the molecular mechanisms linking volume overload to arrhythmogenic remodeling remain poorly understood. Although fibrosis has long been considered the primary substrate for AF, increasing evidence suggests that fibroblast heterogeneity and cell-cell interactions may play important roles in disease progression. Methods: MR was created endovascularly by chordal avulsion in 12 dogs with 6 controls. AF inducibility was assessed by transvenous burst pacing, left atrial volume by echocardiography, and collagen content by Masson trichrome and picrosirius red staining. Single-nucleus RNA sequencing (snRNA-seq) was performed on left atrial posterior wall tissue from control, 4-week, and 6-month MR animals. Fibroblast subpopulations and fibroblast-cardiomyocyte communication were analyzed and markers validated by RNA in situ hybridization in all 18 animals. Results: MR resulted in progressive left atrial dilation, but neither the change in left atrial volume from baseline nor total collagen burden correlated with the inducibility of AF (n=6 each). SnRNA-seq resolved seven major cardiac cell populations and identified four transcriptionally distinct fibroblast populations (NOX4/GRIA4, PCOLCE2, ADRB2/HCN1, PTX3/ICAM1). Fibroblast composition shifted markedly: matrix-associated PCOLCE2 fibroblasts starkly declined by 6 months, whereas inflammatory-associated PTX3/ICAM1 fibroblasts expanded stepwise over time. Cardiomyocyte-to-fibroblast signaling, dominated by PTPRM and LAMA2, was progressively redirected toward PTX3/ICAM1 fibroblasts. RNAscope confirmed a stepwise rise in ICAM1 transcripts and higher ICAM1 in AF-inducible than non-inducible animals. Conclusions: In a canine model of MR, the inducibility of AF was associated with fibroblast state remodeling rather than with atrial dilation or collagen burden. Progressive expansion of inflammatory-associated PTX3/ICAM1 fibroblasts, together with reorganized fibroblast-cardiomyocyte signaling, defines a candidate arrhythmogenic mechanism and therapeutic target in MR.

physiology↗

bioRxiv2025

Single-Cell Resolution of Individual Variation in Hypothalamic Neurons Allows Targeted Manipulation Affecting Social Motivation

Despite decades of research, connecting molecular and cellular phenotypes to complex behavioral traits remains an elusive goal1. Social motivation exhibits individual trait variation2, which we hypothesize is mediated by molecular and cellular variability across hypothalamic neurons. To test this, we generated single-nucleus RNA-sequencing profiles3,4 of >120,000 neurons from tuberal hypothalamus and adjacent thalamus in 36 mice, balanced across sex and autism-associated mutation5, with all mice assessed for social motivation2. First, we show that molecular activation patterns predict behavior across individuals: specifically, activation of paraventricular Agtr1a+ (angiotensin receptor 1a) neurons predicted reduced social behavior. Subsequent inhibition of AGTR1A with telmisartan--an FDA-approved antihypertensive6--improved social orienting. Second, we show natural variation in neuronal proportions--likely arising from stochastic developmental events7--is sufficient to shape adult behavior even among genetically-identical individuals: we identified multiple neuronal populations whose relative abundance predicted social reward-seeking behavior. Chemogenetic inhibition of one such population, Nxph4+ neurons of the postero-lateral hypothalamus8, suppressed multiple aspects of social motivation. This work establishes proof-of-principle for an approach where single-cell genomics precisely maps neural substrates governing behavior. This approach revealed that stochastic variations in neuronal architecture deterministically influence social motivation, and enabled identification of therapeutically-actionable targets with immediate translational potential for disorders with social deficits.

genetics↗

bioRxiv2024

Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model

Schinzel-Giedion Syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function mutations in the SETBP1 gene. While previous studies determined multiple roles for how SETBP1 and associated pathways may cause disease manifestation, they have not assessed whether cell-type-specific alternative splicing (AS) plays a role in SGS. We quantified gene and splice junction (SJ) expression from snRNA-seq data we previously generated from the cerebral cortex and the kidney of an atypical Setbp1S858R SGS patient variant (n = 3) and wild-type (n = 3) mice. We performed pseudobulk differential gene expression and SJ usage (SJU) analyses across cell types and conditions. We identified 33 and 62 genes with statistically significant alterations in SJU in the brain and the kidney, respectively. Astrocytes and T cells had the most genes with cell-type-specific changes in SJU (n = 6 each) in the brain and kidney, respectively. We identified significant SJU in a member of the heterogeneous nuclear ribonucleoprotein family, Hnrnpa2b1. These findings were cell-type-specific for inhibitory neurons in the cerebral cortex and cell-type-agnostic in the kidney, suggesting tissue-specificity of AS in Setbp1S858R mice. To broaden the impact of our results for the rare disease community, we developed a point-and-click web application as a resource for users to explore single-cell resolution changes in the presence of Setbp1S858R at the gene and splice junction level. Overall, we find that AS may be implicated in a tissue- and cell-type-specific manner in the cerebral cortex and kidney of Setbp1S858R mice.

genomics↗

bioRxiv2024

Long-read RNA sequencing identifies region- and sex-specific C57BL/6J mouse brain mRNA isoform expression and usage

Alternative splicing (AS) contributes to the biological heterogeneity between species, sexes, tissues, and cell types. Many diseases are either caused by alterations in AS or by alterations to AS. Therefore, measuring AS accurately and efficiently is critical for assessing molecular phenotypes, including those associated with disease. Long-read sequencing enables more accurate quantification of differentially spliced isoform expression than short-read sequencing approaches, and third-generation platforms facilitate high-throughput experiments. To assess differences in AS across the cerebellum, cortex, hippocampus, and striatum by sex, we generated and analyzed Oxford Nanopore Technologies (ONT) long-read RNA sequencing (lrRNA-Seq) C57BL/6J mouse brain cDNA libraries. From >85 million reads that passed quality control metrics, we calculated differential gene expression (DGE), differential transcript expression (DTE), and differential transcript usage (DTU) across brain regions and by sex. We found significant DGE, DTE, and DTU across brain regions and that the cerebellum had the most differences compared to the other three regions. Additionally, we found region-specific differential splicing between sexes, with the most sex differences in DTU in the cortex and no DTU in the hippocampus. We also report on two distinct patterns of sex DTU we observed, sex-divergent and sex-specific, that could potentially help explain sex differences in the prevalence and prognosis of various neurological and psychiatric disorders in future studies. Finally, we built a Shiny web application for researchers to explore the data further. Our study provides a resource for the community; it underscores the importance of AS in biological heterogeneity and the utility of long-read sequencing to better understand AS in the brain.

genomics↗

bioRxiv2023

Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes

BackgroundPrevious pharmacovigilance studies and a retroactive review of cancer clinical trial studies identified that women were more likely to experience drug adverse events (i.e., any unintended effects of medication), and men were more likely to experience adverse events that resulted in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors not entirely understood, including differences in body mass, hormones, pharmacokinetics, and liver drug metabolism enzymes and transporters. MethodsWe first identified drugs associated with SBAEs from the FDA Adverse Event Reporting System (FAERS) database. Next, we evaluated sex-specific gene expression of the known drug targets and metabolism enzymes for those SBAE-associated drugs. We also constructed sex-specific tissue gene-regulatory networks to determine if these known drug targets and metabolism enzymes from the SBAE-associated drugs had sex-specific gene-regulatory network properties and predicted regulatory relationships. ResultsWe identified liver-specific gene-regulatory differences for drug metabolism genes between males and females, which could explain observed sex differences in pharmacokinetics and pharmacodynamics. In addition, we found that [~]85% of SBAE-associated drug targets had sex-biased gene expression or were core genes of sex- and tissue-specific network communities, significantly higher than randomly selected drug targets. Lastly, we provide the sex-biased drug-adverse event pairs, drug targets, and drug metabolism enzymes as a resource for the research community. ConclusionsOverall, we provide evidence that many SBAEs are associated with drug targets and drug metabolism genes that are differentially expressed and regulated between males and females. These SBAE-associated drug metabolism enzymes and drug targets may be useful for future studies seeking to explain or predict SBAEs.

genomics↗