Biology subjects

Lahue, C.

Publications and source records attributed to Lahue, C..

5 recordsLinked to original sources

bioRxiv2025

A systems genetics approach to uncover mitochondrial drivers of heart failure reveals mitochondria-nuclear cross talk in genetically diverse mouse strains

The contribution of mitochondrial genetics to heart failure is thought to be reciprocal. Its complex traits are influenced by genetic and environmental factors. Genetically diverse mouse strains form a vital repository to uncover the interaction between the mitochondrial and nuclear genomes underlying heart failure due to their traceable genetic origins, maternal lineages and controlled genetic variation. Using systems genetics, we studied this cross-talk in the Collaborative Cross (CC) mice challenged with heart failure (HF). We used 63 strains of CC-mice that grouped into 8 mitochondrial haplotypes and subjected them to HF using isoproterenol (Iso), a beta-adrenergic stimulant that mimics progressive stress induced HF in humans. The Alzet osmotic pumps delivered a consistent dose of the drug for 21 days following which the mice were euthanized for organ collection. A group of mice with saline loaded pumps acted as control (Ctrl). Baseline and end of study echocardiography were recorded for these mice. Bulk RNA sequencing was carried out on the left ventricles and data analyzed on R-studio. The CC-strains showed differences across the haplotypes for organ weights and heart function. Noticeable treatment specific gene expression differences were observed for 34 nuclear encoded genes from MitoCarta3.0 unlike mt-DNA encoded genes that were insignificant after correcting for sex and haplotypes. These genes were associated with multiple metabolic pathways in the cell. Trait-GWAS associations with markers from the mitochondrial genome were observed only for mice from Iso group with cell surface area (p = 6.19e-06) and change in ejection fraction (p = 9.22e-05) as top hits under FWER threshold of 0.01. Cyfip2 was the top candidate gene (p = 2.66e-07) among the 831 hits (47-MitoCarta & 784 other nuclear) based on our trans-eQTL analysis. The eQTL genes influenced critical pathways of OXPHOS, myogenesis, apoptosis etc. Our approach uncovered 24 gene candidates associated with mt-DNA and HF that overlapped with our previous mi-eQTL reports. CC-mice revealed ancestry dependent effects underlying HF for studying mito-nuclear interactions. Despite establishing differences, modeling these interaction needs development of complex cybrid systems to evaluate the bidirectional impact on HF. Author SummaryThe Collaborative Cross (CC) mouse is a genetically diverse population that has been used to study complex diseases. Recently, our group has comprehensively characterized the heart from 63 strains of the CC and reported genetic associations with heart failure (HF). Traditionally, genetic abnormalities underlying a disease are related to the nuclear genome but there exists an alternate genome within the cells, the mitochondrial DNA (mt-DNA), whose contribution is understudied. The mt-DNA of CC mice is maternally derived from the 8 founder strains, and our sequencing data holds this information, allowing us the ability to use them to study the contribution of mitochondrial ancestry (haplotypes) to HF. We found haplotype differences in terms of cardiac function and gene expression (both nuclear and mitochondrial) that were associated with HF. It revealed stress induced changes in the heart (trait and gene expression) linked with regions in the mt-DNA that encode genes involved in oxidative phosphorylation and metabolism. We uncovered 24 high-confidence nuclear gene candidates that agreed with our previous analyses and were associated with regions on the mt-DNA. These findings open up new opportunities to study the CC and advance the understanding of Mito-nuclear interactions in HF pathophysiology.

genetics↗

bioRxiv2025

Genetic Determinants of Heart Failure Susceptibility and Response in the Collaborative Cross Mouse Population

Genetic variation and lived experiences shape how our hearts respond to chronic stress. The specific genetic mechanisms which underly cardiac remodeling, however, are still unclear, due in part to the challenge of accounting for environmental effects in human population studies. To overcome this challenge, we used the Collaborative Cross (CC) mouse population to investigate heritable susceptibility to cardiovascular stress by chronic {beta}-adrenergic receptor stimulation. Across 8 founder and 63 CC lines, we measured cardiac structure and function, organ weights, cell and tissue morphology, and left ventricular gene expression. Genome-wide scans detected 49 genome-wide significant loci, collapsing to 20 unique intervals (nine significant for multiple traits and eleven trait-specific), averaging 12.83 Mb in size. To identify high-confidence candidate genes from these loci, we augmented our trait mapping with associations between loci and gene expression, isoproterenol-dependent transcriptional changes, coding variants drawn from sequencing data, tractability in our in vitro rat cardiomyocyte model, and previously reported protein functions and mouse or human phenotypes. This approach recovered both known regulators, such as Hey2, and new candidates. Functional tests in in vitro models highlight three candidate genes that modulate hypertrophic growth: Abcb10, Mrps5 and Lmod3. Abcb10 knockdown increased cell size at baseline and further with isoproterenol, consistent with loss of a mitochondrial stress-buffering role. Mrps5 knockdown blunted stress-induced hypertrophy. Paradoxical upregulation of Lmod3 after siRNA transfection (validated at the protein level) also attenuated hypertrophy, consistent with reinforcement of actin-assembly control under catecholamine stress. Together, these results reveal heritable pathways of {beta}-adrenergic remodeling in mice and provide an interpretable, translational, and stepwise framework to prioritize candidate genes within broad loci for mechanistic studies of heart failure.

genomics↗

bioRxiv2025

Global Analyses of Genomic and Epigenomic Influences on Gene Expression Reveals Serpina3n as a Major Regulator of Cardiac Gene Expression in Response to Catecholamine Challenge During Heart Failure

Heart failure arises from maladaptive remodeling driven by genetic and epigenetic networks. Using a systems genetics framework, we mapped how DNA variants and CpG methylation shape cardiac transcriptomes during beta adrenergic stress in the Hybrid Mouse Diversity Panel, a cohort of over 100 fully inbred mouse strains. Expression QTLs (eQTLs), methylation QTLs (mQTLs) and methylation-driven eQTLs (emQTLs) were generated from over 13k expressed genes and 200k hypervariable CpGs in left ventricles. We discovered hundreds of regulatory "hotspots" that control large portions of the genome, including several that regulate over 10% of the transcriptome and/or methylome. Approximately 16% of these hotspots overlapped with prior GWAS or EWAS signals. We focus on a hotspot on chromosome 12 and identify the serpine peptidase inhibitor Serpina3n, as the most likely driver gene in this hotspot. Experimental knockdown of Serpina3n in neonatal rat ventricular cardiomyocytes blunted hypertrophy induced by a variety of hypertrophic signals, while altering predicted target expression and modulating the activity of Nppa and Nppb. Together, these findings position Serpina3n as a major regulator of stress-responsive cardiac gene programs, highlighting how integration of genetic and epigenetic signals can pinpoint key drivers of heart failure. Key HighlightsO_LICross-omics hotspot analysis: We identified 286 eQTL, mQTL, and emQTL hotspots in the Hybrid Mouse Diversity Panel, including several hotspots that regulate over 10% of the cardiac transcriptome. C_LIO_LIIntegration with prior GWAS/EWAS: [~]16% of hotspots overlapped with previously reported heart failure hotspots, strengthening their biological relevance. C_LIO_LIDiscovery of Serpina3n as heart failure regulator: A hotspot on chromosome 12 linked to Serpina3n controlled 4-6% of all gene expression and CpG methylation changes in response to isoproterenol. C_LIO_LIFunctional validation: siRNA knockdown of Serpina3n in cardiomyocytes significantly blunted hypertrophy induced by isoproterenol, angiotensin II, and phenylephrine. C_LIO_LIPathway insights: Genes regulated by the Serpina3n hotspot were enriched for mitochondrial function, dilated cardiomyopathy, and hypertrophic signaling pathways, highlighting a mechanistic link to heart failure progression. C_LI

genetics↗

bioRxiv2024

Mapping DNA Methylation to Cardiac Pathologies Induced by Beta-Adrenergic Stimulation in a Large Panel of Mice

BackgroundHeart failure (HF) is a leading cause of morbidity and mortality worldwide, with over 18 million deaths annually. Despite extensive research, genetic and environmental factors contributing to HF remain complex and poorly understood. Recent studies suggest that epigenetic modifications, such as DNA methylation, may play a crucial role in regulating HF-associated phenotypes. In this study, we leverage the Hybrid Mouse Diversity Panel (HMDP), a cohort of over 100 inbred mouse strains, to investigate the role of DNA methylation in HF progression. ObjectiveWe aim to identify epigenetic modifications associated with HF by integrating DNA methylation data with gene expression and phenotypic traits. Using isoproterenol (ISO)-induced cardiac hypertrophy and failure in HMDP mice, we explore the relationship between methylation patterns and HF susceptibility. MethodsWe performed reduced representational bisulfite sequencing (RRBS) to capture DNA methylation at single-nucleotide resolution in the left ventricles of 90 HMDP mouse strains under both control and ISO-treated conditions. We identified differentially methylated regions (DMRs) and performed an epigenome-wide association study (EWAS) using the MACAU algorithm. We identified likely candidate genes within each locus through integration of our results with previously reported sequence variation, gene expression, and HF-related phenotypes. In vitro approaches were employed to validate key findings, including gene knockdown experiments in neonatal rat ventricular myocytes (NRVMs). We also examined the effects of preventing DNA methyltransferase activity on HF progression. ResultsOur EWAS identified 56 CpG loci significantly associated with HF phenotypes, including 18 loci where baseline DNA methylation predicted post-ISO HF progression. Key candidate genes, such as Prkag2, Anks1, and Mospd3, were identified based on their epigenetic regulation and association with HF traits. In vitro follow-up on a number of genes confirmed that knockdown of Anks1 and Mospd3 in NRVMs resulted in significant alterations in cell size and blunting of ISO-induced hypertrophy, demonstrating their functional relevance in HF pathology. Furthermore, treatment with the DNA methyltransferase inhibitor RG108 in ISO-treated BTBRT mice significantly reduced cardiac hypertrophy and preserved ejection fraction compared to mice only treated with ISO, highlighting the therapeutic potential of targeting DNA methylation in HF. Differential expression analysis revealed that RG108 treatment restored the expression of several methylation-sensitive genes, further supporting the role of epigenetic regulation in HF. ConclusionOur study demonstrates a clear interplay between DNA methylation, gene expression, and HF-associated phenotypes. We identified several novel epigenetic loci and candidate genes that contribute to HF progression, offering new insights into the molecular mechanisms of HF. These findings underscore the importance of epigenetic regulation in cardiac disease and suggest potential therapeutic strategies for modifying HF outcomes through targeting DNA methylation.

genomics↗

bioRxiv2022

Cardiomyocyte ploidy is dynamic during postnatal development and varies across genetic backgrounds

Somatic polyploidization, an adaptation by which cells increase their DNA content to support cell and organ growth, is observed in many mammalian cell types, including cardiomyocytes. Although polyploidization is beneficial in many contexts, progression to a polyploid state is often accompanied by a loss of proliferative capacity. Recent work suggests that heterogeneity in cardiomyocyte ploidy is highly influenced by genetic diversity. However, the developmental course by which cardiomyocytes reach their final ploidy state has only been investigated in select genetic backgrounds. Here, we assessed cardiomyocyte number, cell cycle activity, and ploidy dynamics across two divergent inbred mouse strains; C57Bl/6J and A/J. Both strains are born and reach adulthood with a comparable number of cardiomyocytes, however the end composition of ploidy classes and developmental progression to reach the final state and number differ substantially. In addition to corroborating previous findings that identified Tnni3k as a mediator of cardiomyocyte ploidy, we also uncover a novel role for Runx1 and Tnni3k in ploidy dynamics and cardiomyocyte cytokinesis. These data provide novel insight into the developmental path to cardiomyocyte ploidy states and challenge the paradigm that polyploidization and hypertrophy are the only mechanisms for growth in the mouse heart after the first week of life.

developmental biology↗