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Transverse Aortic Constriction in Mice
Published on: April 21, 2010
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Dot1L Promotes Stress-Induced Cardiac Hypertrophy in Mice via Tbx6
Jiao Liu1,2, Yuxuan Jin2, Shengkai Zuo1,3
1Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences (J.L., S.Z., C.M., B.W., D.H., Q.L., Y.Y.), Tianjin Medical University, China.
Circulation Research
|June 30, 2025
Summary
Targeting Dot1L, a histone methyltransferase, may treat cardiac hypertrophy. Upregulation of Dot1L and H3K79 methylation promotes cardiac hypertrophy by increasing Tbx6 expression, suggesting a therapeutic target for heart failure.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Molecular Medicine
Background:
- Pathological cardiac hypertrophy leads to heart failure, with no effective treatments.
- Epigenetic alterations, particularly histone modifications, are involved in cardiac hypertrophy.
- The precise mechanisms underlying these epigenetic changes remain unclear.
Purpose of the Study:
- To investigate the role of Dot1L (disruptor of telomeric silencing 1-like) and H3K79 methylation in cardiac hypertrophy.
- To identify the molecular targets and pathways regulated by Dot1L in the stressed heart.
- To evaluate Dot1L as a potential therapeutic target for heart failure.
Main Methods:
- Utilized nano-HPLC-MS/MS to analyze histone modifications.
- Generated cardiomyocyte-specific Dot1L knockout and transgenic mice.
- Employed transverse aortic constriction and isoproterenol infusion to induce cardiac stress.
- Combined RNA-sequencing and ChIP-sequencing to identify Dot1L targets.
- Validated findings in primary neonatal rat ventricle myocytes.
Main Results:
- Histone H3K79 dimethylation and Dot1L were upregulated in cardiac hypertrophy models and human samples.
- Dot1L ablation protected against pressure overload-induced cardiac hypertrophy.
- Dot1L-mediated H3K79 methylation promoted Tbx6 expression in stressed cardiomyocytes.
- Tbx6 knockdown abolished Dot1L-induced cardiac hypertrophy.
- Dot1L inhibitor SGC0946 treatment improved cardiac hypertrophy.
Conclusions:
- The Dot1L-H3K79 dimethylation-Tbx6 axis drives pressure overload-induced cardiac hypertrophy.
- Targeting Dot1L represents a promising therapeutic strategy for heart failure.
