Biology subjects

Gwynn, C.

Publications and source records attributed to Gwynn, C..

2 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↗

bioRxiv2026

The SMYD1 p.Asn101Ser is a partial loss-of-function variant that impairs mitochondrial function and leads to early-onset cardiomyopathy.

Infantile cardiomyopathies are rare, life-threatening disorders for which genetic diagnosis has been accelerated by next-generation sequencing approaches, including gene panel, exome, and genome sequencing. However, determining the functional consequences of identified variants remains a major challenge. Variants in SMYD1, a striated muscle-specific lysine methyltransferase critical for cardiac development and mitochondrial function, have only recently been linked to human cardiomyopathy. Here, we functionally characterize a homozygous SMYD1 variant (c.302A>G; p.Asn101Ser) identified in a patient with severe early-onset cardiomyopathy requiring cardiac transplantation. Structural modeling predicts that the N101S substitution perturbs a highly conserved residue near the cofactor binding pocket within SMYD1s catalytic domain, disrupting local interactions and modestly destabilizing the protein. Consistent with these predictions, in vitro studies demonstrate that the N101S variant impairs mitochondrial respiratory capacity in myocytes. Quantification of SMYD1 protein levels in patient cardiac tissue revealed increased SMYD1 abundance, suggesting that the N101S variant results in functional impairment rather than protein instability and may trigger compensatory upregulation of SMYD1 expression. Together, these findings support a hypomorphic mechanism in which the N101S variant disrupts SMYD1 activity, leading to mitochondrial dysfunction and cardiomyopathy. This study provides mechanistic insight into SMYD1-associated cardiomyopathy and highlights the importance of integrating genetic, structural, and functional analyses to establish the pathogenicity of rare variants. New & NoteworthyThis study provides the first functional characterization of the cardiomyopathy-associated SMYD1 N101S variant identified in a child with severe infantile cardiomyopathy. Structural modeling predicts reduced protein stability, while cellular assays demonstrate impaired mitochondrial respiratory function, supporting a hypomorphic effect. These findings establish a mechanistic link between SMYD1 dysfunction and infantile cardiomyopathy and highlight the importance of integrating genomic and functional approaches in rare cardiovascular disease.

cell biology↗