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Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):E7871-E7880. doi: 10.1073/pnas.1800680115. Epub 2018 Jul 30.

Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart.

Author information

1
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112; junco.warren@utah.edu.
2
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84102.
3
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112.
4
Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103.
5
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84103.
6
Associated Regional and University Pathologists, Inc. Laboratories, Salt Lake City, UT 84108.
7
Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112.
8
Department of Biochemistry, University of Utah, Salt Lake City, UT 84112.
9
Metabolic Phenotyping Core Facility, University of Utah, Salt Lake City, UT 84112.
10
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.
11
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112.
12
Genome Center-Metabolomics, University of California, Davis, CA 95616.
13
Biochemistry Department, King Abdulaziz University, 21589 Jeddah, Saudi Arabia.
14
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712.
15
The Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712.
16
Department of Bioengineering, University of Utah, Salt Lake City, UT 84112.

Abstract

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.

KEYWORDS:

PGC-1a; Smyd1; heart; metabolism; systems biology

PMID:
30061404
PMCID:
PMC6099878
DOI:
10.1073/pnas.1800680115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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