Key result
Dot1L ablation or inhibition protects against induced cardiac hypertrophy in mice.
Why the study?
Pathological cardiac hypertrophy leads to heart failure without effective treatments, and the detailed mechanisms of implicated epigenetic dysregulation, including histone modification alterations, remain incompletely elucidated.
Does Dot1L inhibition prevent stress-induced cardiac hypertrophy in preclinical models?
Does Dot1L inhibition prevent stress-induced cardiac hypertrophy in preclinical models?
Dot1L promotes stress-induced cardiac hypertrophy via Tbx6, identifying Dot1L inhibition as a potential novel therapeutic target for heart failure.
Targeting Dot1L may attenuate stress-induced hypertrophy in models; leaves open clinical translation of H3K79 methylation inhibition.
BACKGROUND: Sustained pathological cardiac hypertrophy eventually leads to heart failure; however, there is currently no effective therapeutic approach. Epigenetic dysregulation, including histone modification alterations, is implicated in cardiac hypertrophy development. Yet, the detailed mechanisms are not completely elucidated. METHODS: Nano-HPLC-MS/MS (nano-scale high-performance liquid chromatography-tandem mass spectrometry) was conducted to analyze histone modifications. Cardiomyocyte-specific Dot1L (disruptor of telomeric silencing 1-like) knockout and transgenic mice were generated to evaluate the function of Dot1L in cardiac hypertrophy. Stress was induced in mice by transverse aortic constriction or continuous isoproterenol infusion. RNA-sequencing and chromatin immunoprecipitation sequencing were combined and analyzed to identify the direct transcriptional target of Dot1L, which was verified by multiple molecular biological methodologies. Primary neonatal rat ventricle myocytes were used to identify potential targets and study the molecular mechanisms. RESULTS: Histone H3K79 dimethylation and its specific methyltransferase Dot1L were upregulated in hypertrophic stimuli-treated cardiomyocytes, cardiac tissues from pressure overload-stressed mice, and patients with hypertrophic cardiomyopathy. The ablation of Dot1L in cardiomyocytes of adult mice protected against pressure overload-induced hypertrophy. Chromatin immunoprecipitation sequencing assay and genome-wide transcriptional analysis showed that Dot1L-catalyzed H3K79 dimethylation promoted the expression of transcription factor Tbx6 in stressed neonatal rat ventricle myocytes. Knockdown of Tbx6 (T-box transcription factor 6) abolished Dot1L overexpression-exaggerated cardiac hypertrophy in mice in response to pressure overload. The Dot1L inhibitor SGC0946 treatment markedly improved isoproterenol-induced cardiac hypertrophy in mice. CONCLUSIONS: Dot1L-H3K79 dimethylation-Tbx6 axis facilitates pressure overload-induced cardiac hypertrophy. Targeting Dot1L may be a promising therapeutic strategy for heart failure.
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Liu et al. (2025) studied Cardiac hypertrophy. Dot1L ablation or inhibition (SGC0946) vs. Control was evaluated on Cardiac hypertrophy. Ablation of Dot1L or treatment with the Dot1L inhibitor SGC0946 protected against pressure overload- or isoproterenol-induced cardiac hypertrophy in mice.
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