Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, 185 South Orange Ave., MSB G609, Newark, NJ, 07103, USA.
Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Sci Rep. 2022 Aug 26;12(1):14576. doi: 10.1038/s41598-022-18885-3.
PERM1 (PGC-1/ERR-induced regulator in muscle 1) is a muscle-specific protein induced by PGC-1 and ERRs. Previous studies have shown that PERM1 promotes mitochondrial biogenesis and metabolism in cardiomyocytes in vitro. However, the role of endogenous PERM1 in the heart remains to be investigated with loss-of-function studies in vivo. We report the generation and characterization of systemic Perm1 knockout (KO) mice. The baseline cardiac phenotype of the homozygous Perm1 KO mice appeared normal. However, RNA-sequencing and unbiased pathway analyses showed that homozygous downregulation of PERM1 leads to downregulation of genes involved in fatty acid and carbohydrate metabolism in the heart. Transcription factor binding site analyses suggested that PPARα and PGC-1α are involved in changes in the gene expression profile. Chromatin immunoprecipitation assays showed that PERM1 interacts with the proximal regions of PPAR response elements (PPREs) in endogenous promoters of genes involved in fatty acid oxidation. Co-immunoprecipitation and reporter gene assays showed that PERM1 promoted transcription via the PPRE, partly in a PPARα and PGC-1α dependent manner. These results suggest that endogenous PERM1 is involved in the transcription of genes involved in fatty acid oxidation through physical interaction with PPARα and PGC-1α in the heart in vivo.
PERM1（PGC-1/ERR 诱导的肌肉 1 调节剂）是一种由 PGC-1 和 ERR 诱导的肌肉特异性蛋白。先前的研究表明，PERM1 可促进体外心肌细胞中线粒体的生物发生和代谢。然而，内源性 PERM1 在心脏中的作用仍需通过体内功能丧失研究来研究。我们报告了系统性 Perm1 敲除（KO）小鼠的产生和特征。纯合子 Perm1 KO 小鼠的基线心脏表型似乎正常。然而，RNA 测序和无偏通路分析表明，PERM1 的同源下调导致心脏中参与脂肪酸和碳水化合物代谢的基因下调。转录因子结合位点分析表明，PPARα 和 PGC-1α 参与了基因表达谱的变化。染色质免疫沉淀测定表明，PERM1 与参与脂肪酸氧化的基因的内源性启动子中的 PPAR 反应元件（PPRE）的近端区域相互作用。共免疫沉淀和报告基因测定表明，PERM1 通过 PPRE 促进转录，部分依赖于 PPARα 和 PGC-1α。这些结果表明，内源性 PERM1 通过与体内心脏中的 PPARα 和 PGC-1α 物理相互作用参与参与脂肪酸氧化的基因的转录。
