Open AccessPerm1 regulates cardiac energetics as a downstream target of the histone methyltransferase Smyd1
Author(s) -
Shinichi Oka,
Amira D. Sabry,
A Horiuchi,
Keiko M. Cawley,
Sean O’Very,
Maria A. Zaitsev,
Thirupura S. Shankar,
Jaemin Byun,
Risa Mukai,
Xiaoyong Xu,
Natalia S. Torres,
Anil Kumar,
Masayuki Yazawa,
Ling Jing,
Iosif Taleb,
Yukio Saijoh,
Stavros G. Drakos,
Junichi Sadoshima,
Jason G. Warren
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0234913
Subject(s) - downregulation and upregulation , microbiology and biotechnology , chromatin immunoprecipitation , transcriptional regulation , biology , histone , regulator , gene knockdown , myocyte , promoter , methyltransferase , gene expression , chemistry , gene , methylation , biochemistry
The transcriptional regulatory machinery in mitochondrial bioenergetics is complex and is still not completely understood. We previously demonstrated that the histone methyltransferase Smyd1 regulates mitochondrial energetics. Here, we identified Perm1 ( P PARGC-1 and E SRR-induced r egulator, m uscle specific 1 ) as a downstream target of Smyd1 through RNA-seq. Chromatin immunoprecipitation assay showed that Smyd1 directly interacts with the promoter of Perm1 in the mouse heart, and this interaction was significantly reduced in mouse hearts failing due to pressure overload for 4 weeks, where Perm1 was downregulated (24.4 ± 5.9% of sham, p<0.05). Similarly, the Perm1 protein level was significantly decreased in patients with advanced heart failure (55.2 ± 13.1% of donors, p<0.05). Phenylephrine (PE)-induced hypertrophic stress in cardiomyocytes also led to downregulation of Perm1 (55.7 ± 5.7% of control, p<0.05), and adenovirus-mediated overexpression of Perm1 rescued PE-induced downregulation of estrogen-related receptor alpha (ERRα), a key transcriptional regulator of mitochondrial energetics, and its target gene, Ndufv1 (Complex I). Pathway enrichment analysis of cardiomyocytes in which Perm1 was knocked-down by siRNA (siPerm1), revealed that the most downregulated pathway was metabolism. Cell stress tests using the Seahorse XF analyzer showed that basal respiration and ATP production were significantly reduced in siPerm1 cardiomyocytes (40.7% and 23.6% of scrambled-siRNA, respectively, both p<0.05). Luciferase reporter gene assay further revealed that Perm1 dose-dependently increased the promoter activity of the ERR α gene and known target of ERRα, Ndufv1 (Complex I). Overall, our study demonstrates that Perm1 is an essential regulator of cardiac energetics through ERRα, as part of the Smyd1 regulatory network.