Biology subjects

Travers, J. G.

Publications and source records attributed to Travers, J. G..

5 recordsLinked to original sources

bioRxiv2026

T cell-derived IFNγ instructs ECM crosslinking by cardiac fibroblasts through LOXL3 in experimental cardiometabolic HFpEF

BackgroundHeart failure with preserved ejection fraction (HFpEF) is a major clinical challenge characterized by diastolic dysfunction. Left ventricular stiffening and inflammation are hallmarks of HFpEF, yet the contribution of extracellular matrix (ECM) stiffness and the immune-stromal mechanisms driving ECM stiffening in cardiometabolic HFpEF remain poorly understood. MethodsWe used the murine "2-hit model" of cardiometabolic HFpEF, in which the combination of high fat diet and hypertension induced by L-NAME causes diastolic dysfunction. We evaluated diastolic function by echocardiography and ECM mechanics by uniaxial tensile testing of decellularized cardiac tissue. Functional in vivo studies included genetic depletion of T cells, interferon-{gamma} (IFN{gamma}) knockout mice, and pharmacological lysyl oxidase inhibition. We combined co-cultures of CD4+ T cells and cardiac fibroblasts (CFB) with mechanical testing of cardiac ECM and molecular biology to elucidate cellular and molecular mechanisms. ResultsLeft ventricular ECM stiffness strongly correlated with impaired diastolic function in experimental cardiometabolic HFpEF. Cardiac CD4 T cell infiltration was required for ECM stiffening and upregulation of lysyl oxidase enzymes in CFB. CD4+ T cell-derived IFN{gamma} was both necessary and sufficient to induce LOXL3 in CFB, which increased ECM stiffness in vitro. Mechanistically, IFN{gamma} signaling activated hypoxia-inducible factor-1 (HIF1) in CFB, driving LOXL3 expression and subsequent collagen crosslinking. Genetic or pharmacologic disruption of this IFN{gamma}-HIF1-LOXL3 axis in vivo attenuated adverse ECM remodeling and improved diastolic function. ConclusionsCD4 T cells promote pathological ECM stiffening in cardiometabolic HFpEF through IFN{gamma}-mediated, LOXL3-dependent ECM crosslinking by CFB. Targeting this immune-stromal pathway may offer a novel therapeutic strategy for HFpEF.

pathology↗

bioRxiv2025

Deuterium labeling enables proteome wide turnover kinetics analysis in cell culture

The half-life of proteins is tightly regulated and underlies many cellular processes. It remains unclear the extent to which proteins are dynamically synthesized and degraded in different cell types and cell states. We introduce an improved D2O labeling workflow and apply it to examine the landscape of protein turnover in pluripotent and differentiating human induced pluripotent stem cells (hiPSC). The majority of hiPSC proteins show minimal turnover beyond cell doubling rates, but we also identify over 100 new fast-turnover proteins not previously described as short-lived. These include proteins that function in cell division and cell cycle checkpoints, that are enriched in APC/C and SPOP degrons, and that are depleted upon pluripotency exit. Differentiation rapidly shifts the set of fast-turnover proteins toward including RNA binding and splicing proteins. The ability to identify fast-turnover proteins in different cell cultures also facilitates secretome analysis, as exemplified by studies of hiPSC-derived cardiac myocytes and primary human cardiac fibroblasts. The presented workflow is broadly applicable to protein turnover studies in diverse primary, pluripotent, and transformed cells.

biochemistry↗

bioRxiv2024

Logic-based machine learning predicts how escitalopram inhibits cardiomyocyte hypertrophy

IntroductionCardiomyocyte hypertrophy is a key clinical predictor of heart failure. High-throughput and AI-driven screens have potential to identify drugs and downstream pathways that modulate cardiomyocyte hypertrophy. MethodsHere we developed LogiRx, a logic-based mechanistic machine learning method that predicts drug-induced pathways. We applied LogiRx to discover how drugs discovered in a previous compound screen attenuate cardiomyocyte hypertrophy. We experimentally validated LogiRx predictions in neonatal cardiomyocytes, adult mice, and two patient databases. ResultsUsing LogiRx, we predicted anti-hypertrophic pathways for 7 drugs currently used to treat non-cardiac disease. We experimentally validated that escitalopram (Lexapro) and mifepristone inhibit hypertrophy of cultured cardiomyocytes in two contexts. The LogiRx model predicted that escitalopram prevents hypertrophy through an "off-target" serotonin receptor/PI3K{gamma} pathway, mechanistically validated using additional investigational drugs. Further, escitalopram reduced cardiomyocyte hypertrophy in a mouse model of hypertrophy and fibrosis. Finally, mining of both FDA and University of Virginia databases showed that patients with depression on escitalopram have a lower incidence of cardiac hypertrophy than those prescribed other serotonin reuptake inhibitors that do not target the serotonin receptor. ConclusionMechanistic machine learning by LogiRx discovers drug pathways that perturb cell states, which may enable repurposing of escitalopram and other drugs to limit cardiac remodeling through "off-target" pathways.

systems biology↗

bioRxiv2023

Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis

Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1-positive cells identified a large enhancer proximal to Interleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.

molecular biology↗

bioRxiv2020

A Transcriptional Switch Governing Fibroblast Plasticity Underlies Reversibility of Chronic Heart Disease

In diseased organs, stress-activated signaling cascades alter chromatin, triggering broad shifts in transcription and cell state that exacerbate pathology. Fibroblast activation is a common stress response that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains poorly understood1,2. Pharmacologic inhibition of the BET family of transcriptional coactivators alleviates cardiac dysfunction and associated fibrosis, providing a tool to mechanistically interrogate maladaptive fibroblast states and modulate their plasticity as a potential therapeutic approach3-8. Here, we leverage dynamic single cell transcriptomic and epigenomic interrogation of heart tissue with and without BET inhibition to reveal a reversible transcriptional switch underlying stress-induced fibroblast activation. Transcriptomes of resident cardiac fibroblasts demonstrated robust and rapid toggling between the quiescent fibroblast and activated myofibroblast state in a manner that directly correlated with BET inhibitor exposure and cardiac function. Correlation of single cell chromatin accessibility with cardiac function revealed a novel set of reversibly accessible DNA elements that correlated with disease severity. Among the most dynamic elements was an enhancer regulating the transcription factor MEOX1, which was specifically expressed in activated myofibroblasts, occupied putative regulatory elements of a broad fibrotic gene program, and was required for TGF{beta}-induced myofibroblast activation. CRISPR interference of the most dynamic cis-element within the enhancer, marked by nascent transcription, prevented TGF{beta}-induced activation of Meox1. These findings identify MEOX1 as a central regulator of stress-induced myofibroblast activation associated with cardiac dysfunction. The plasticity and specificity of the BET-dependent regulation of MEOX1 in endogenous tissue fibroblasts provides new trans- and cis- targets for treating fibrotic disease.

molecular biology↗