Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart
| Autor: | Oliver Fiehn, Yong Hwan Han, Li Wang, Bucky K. Lozier, Alexey V. Zaitsev, Keiko M. Cawley, Haley O. Tucker, Dane W. Barton, Shin Ichi Oka, Tatiana Yuzyuk, Marta W. Szulik, Sihem Boudina, Aman Makaju, James E. Cox, Sarah Franklin, Anil Kumar, Christopher M. Tracy, June García Llana, Junco S. Warren, Amira D. Sabry, Mickey R. Miller |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Histone H3 Lysine 4 Knockout Muscle Proteins heart Cardiovascular Mitochondria Heart Muscle hypertrophy Smyd1 03 medical and health sciences Mice medicine Genetics Gene silencing Animals 2.1 Biological and endogenous factors PPAR alpha Aetiology Regulation of gene expression Mice Knockout Gene knockdown Multidisciplinary Retinoid X Receptor alpha Chemistry Myocardium Cardiac muscle systems biology Histone-Lysine N-Methyltransferase medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology Mitochondria DNA-Binding Proteins 030104 developmental biology medicine.anatomical_structure Heart Disease PNAS Plus Gene Expression Regulation Histone methyltransferase Heart failure Histone Methyltransferases PGC-1a Energy Metabolism metabolism Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 115, iss 33 |
| Popis: | Smyd1, a muscle-specific histone methyltransferase, has established roles in skeletal and cardiac muscle development, but its role in the adult heart remains poorly understood. Our prior work demonstrated that cardiac-specific deletion of Smyd1 in adult mice (Smyd1-KO) leads to hypertrophy and heart failure. Here we show that down-regulation of mitochondrial energetics is an early event in these Smyd1-KO mice preceding the onset of structural abnormalities. This early impairment of mitochondrial energetics in Smyd1-KO mice is associated with a significant reduction in gene and protein expression of PGC-1α, PPARα, and RXRα, the master regulators of cardiac energetics. The effect of Smyd1 on PGC-1α was recapitulated in primary cultured rat ventricular myocytes, in which acute siRNA-mediated silencing of Smyd1 resulted in a greater than twofold decrease in PGC-1α expression without affecting that of PPARα or RXRα. In addition, enrichment of histone H3 lysine 4 trimethylation (a mark of gene activation) at the PGC-1α locus was markedly reduced in Smyd1-KO mice, and Smyd1-induced transcriptional activation of PGC-1α was confirmed by luciferase reporter assays. Functional confirmation of Smyd1’s involvement showed an increase in mitochondrial respiration capacity induced by overexpression of Smyd1, which was abolished by siRNA-mediated PGC-1α knockdown. Conversely, overexpression of PGC-1α rescued transcript expression and mitochondrial respiration caused by silencing Smyd1 in cardiomyocytes. These findings provide functional evidence for a role of Smyd1, or any member of the Smyd family, in regulating cardiac energetics in the adult heart, which is mediated, at least in part, via modulating PGC-1α. |
| Databáze: | OpenAIRE |
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