Biology subjects

Miller, M. R.

Publications and source records attributed to Miller, M. R..

4 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte-specific loss of Smyd5 leads to a robust activation of inflammatory signaling and heart failure in mice.

Background: Cardiomyocytes respond to stress by undergoing hypertrophic growth driven by dynamic changes in gene expression. Epigenetic mechanisms, including histone methylation, play critical roles in regulating these transcriptional programs, yet the enzymes controlling these modifications during cardiac disease remain largely unknown. The SMYD family of histone methyltransferases regulates gene expression in multiple biological contexts, but the function of SMYD5 in the mammalian heart has never been investigated. Methods: SMYD5 expression was assessed in human heart failure samples and in a mouse model of cardiac hypertrophy. To define its functional role in vivo, we generated inducible cardiomyocyte-specific Smyd5 knockout mice and characterized their cardiac phenotype using molecular, histological, and functional analyses. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) was performed to examine histone H4 lysine 20 trimethylation (H4K20me3) at the Il-6 promoter. Results: SMYD5 expression was altered in diseased human and mouse hearts. Under basal conditions, cardiomyocyte-specific deletion of Smyd5 resulted in baseline structural cardiac remodeling and transcriptional signatures characteristic of pathological stress. Smyd5-deficient hearts exhibited marked inflammatory activation resembling a cytokine storm with immune cell infiltration and heart failure. Notably, Smyd5 knockout mice displayed a 100-fold increase in Il-6 expression, accompanied by a global reduction in H4K20me3. ChIP-qPCR analysis of the Il-6 promoter, together with loss- and gain-of-function analysis of SMYD5, supports a direct epigenetic role of SMYD5 in regulating Il-6 expression through H4K20me3 in cardiomyocytes. Conclusions: SMYD5 is a previously unrecognized epigenetic regulator of cardiac homeostasis that restrains inflammatory signaling in cardiomyocytes under normal conditions. Loss of Smyd5 disrupts H4K20me3, leading to derepression of Il-6 in cardiomyocytes and a robust inflammatory response characterized by immune cell recruitment and fibrosis, accompanied by rapid progression of cardiac remodeling and heart failure. These findings identify SMYD5 as a critical regulator of intrinsic cardiomyocyte inflammatory signaling and reveal a novel chromatin-based mechanism contributing to inflammatory cardiomyopathies.

molecular biology↗

bioRxiv2018

Flow regulation associated with decreased genetic health of a river-breeding frog species

River regulation or flow modification--the hydrological alteration of flow by dams and diversions--has been implicated as a cause of fundamental change to downstream aquatic ecosystems. Flow modification changes the patterns and functionality of the natural flow regime, and has the potential to restrict population connectivity and gene flow in river-dependent organisms. Since population connectivity and the maintenance of genetic diversity are fundamental drivers of long-term persistence, understanding the extent flow modification impacts these critical attributes of genetic health is an important goal for long-term conservation. Foothill yellow-legged frogs (Rana boylii) were historically abundant throughout many western rivers but have declined since the onset of regulation. However, the extent to which R. boylii populations in rivers with altered flow regimes are maintaining connectivity and genetic diversity is unknown. Here we use genetic methods to investigate the impacts of flow alteration on R. boylii to explore their potential for long-term persistence under continued flow modification. We found R. boylii in rivers with flow modification showed striking patterns of isolation and trajectories of genetic diversity loss relative to unregulated rivers. For example, flow modification explained the greatest amount of variance in population genetic differentiation compared with other covariates including geographic distance. Importantly, patterns of connectivity and genetic diversity loss were observed regardless of flow alteration level but were most prominent in locations with the greatest flow modification intensity. Although our results do not bode well for long-term persistence of R. boylii populations under current flow regulation regimes, they do highlight the power of genetic monitoring for assessing population health in aquatic organisms.

ecology↗

bioRxiv2018

Anthropogenic habitat alteration leads to rapid loss of adaptive variation and restoration potential in wild salmon populations

Phenotypic variation is critical for the long-term persistence of species and populations. Anthropogenic activities have caused substantial shifts and reductions in phenotypic variation across diverse taxa, but the underlying mechanism (i.e., phenotypic plasticity and/or genetic evolution) and potential to recover previous phenotypic characteristics are unclear. Here we investigate changes in adult migration characteristics of wild salmon populations caused by dam construction and other anthropogenic habitat modifications. Strikingly, we find that dramatic allele frequency change (i.e., genetic evolution) from strong selection at a single locus explains the rapid phenotypic shift observed after recent dam construction. Furthermore, ancient DNA analysis confirms the abundance of a specific allele associated with adult migration type in historical habitat that will soon become accessible through a large restoration (i.e., dam removal) project. However, analysis of contemporary samples suggests the restoration will be challenged by loss of the allele from potential source populations. These results highlight the need to conserve and restore critical adaptive variation before the potential for recovery is lost.

genetics↗

bioRxiv2017

A novel mitochondrial enriched antioxidant protects neurons against acute oxidative stress

Excessive reactive oxygen species (ROS) can damage proteins, lipids, and DNA, which result in cell damage and death. The outcomes can be acute, as seen in stroke, or more chronic as observed in age-related diseases such as Parkinsons disease. Here we investigate the antioxidant ability of a novel synthetic flavonoid, Proxison (7-decyl-3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), using a range of in vitro and in vivo approaches. We show that, while it has radical scavenging ability on par with other flavonoids in a cell-free system, Proxison is orders of magnitude more potent than natural flavonoids at protecting neural cells against oxidative stress and is capable of rescuing damaged cells. The unique combination of a lipophilic hydrocarbon tail with a modified polyphenolic head group promotes efficient cellular uptake and mitochondrial localisation of Proxison. Importantly, in vivo administration of Proxison demonstrated effective and well tolerated neuroprotection against oxidative stress in a zebrafish model of dopaminergic neuronal loss.

cell biology↗