Biology subjects

Davis, K.

Publications and source records attributed to Davis, K..

3 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

The relationship between brain atrophy and cognitive-behavioral symptoms in retired Canadian football players with multiple concussions

Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance. Deformation-based morphometric confirmed smaller bilateral hippocampal volume that were associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age.

neuroscience↗

bioRxiv2017

The medial temporal lobe organizes memory across time and space: Causal evidence from brain stimulation

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects abilities to remember items using view-independent (allocentric) navigation strategies. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.\n\nSignificance StatementNumerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

neuroscience↗