Shi Hangchuan, Chen Si, Meng Fanju W, Ossip Deborah J, Yan Chen, Li Dongmei
Department of Clinical and Translational Research, University of Rochester Medical Center, Rochester, NY, United States.
Department of Public Health Sciences, University of Rochester Medical Center, Rochester, NY, United States.
Front Genet. 2023 Sep 27;14:1264382. doi: 10.3389/fgene.2023.1264382. eCollection 2023.
Physiological and pathological stimuli result in distinct forms of cardiac hypertrophy, but the molecular regulation comparing the two, especially at the DNA methylation level, is not well understood. We conducted an study using human cardiomyocytes exposed to angiotensin II (AngII) and insulin-like growth factor 1 (IGF-1) to mimic pathologically and physiologically hypertrophic heart models, respectively. Whole genome DNA methylation patterns were profiled by the Infinium human MethylationEPIC platform with >850 K DNA methylation loci. Two external datasets were used for comparisons and qRT-PCR was performed for examining expression of associated genes of those identified DNA methylation loci. We detected 194 loci that are significantly differentially methylated after AngII treatment, and 206 significant loci after IGF-1 treatment. Mapping the significant loci to genes, we identified 158 genes corresponding to AngII treatment and 175 genes to IGF-1 treatment. Using the gene-set enrichment analysis, the PI3K-Akt signaling pathway was identified to be significantly enriched for both AngII and IGF-1 treatment. The Hippo signaling pathway was enriched after IGF-1 treatment, but not for AngII treatment. and are components of the PI3K-Akt pathway but have different DNA methylation patterns in response to AngII and IGF-1. qRT-PCR confirmed the different gene expressions of and . Our study is pioneering in profiling epigenome DNA methylation changes in adult human cardiomyocytes under distinct stress conditions: pathological (AngII) and physiological (IGF-1). The identified DNA methylation loci, genes, and pathways might have the potential to distinguish between pathological and physiological cardiac hypertrophy.
生理和病理刺激会导致不同形式的心脏肥大，但对两者的分子调控，尤其是在DNA甲基化水平上的调控，人们还了解得不够透彻。我们进行了一项研究，分别用人心肌细胞暴露于血管紧张素II（AngII）和胰岛素样生长因子1（IGF-1）来模拟病理性和生理性肥大心脏模型。通过Infinium人类甲基化EPIC平台对超过85万个DNA甲基化位点进行全基因组DNA甲基化模式分析。使用两个外部数据集进行比较，并进行qRT-PCR以检测那些已识别的DNA甲基化位点相关基因的表达。我们检测到AngII处理后有194个位点甲基化差异显著，IGF-1处理后有206个显著位点。将这些显著位点映射到基因上，我们确定了与AngII处理相对应的158个基因和与IGF-1处理相对应的175个基因。使用基因集富集分析，发现PI3K-Akt信号通路在AngII和IGF-1处理中均显著富集。Hippo信号通路在IGF-1处理后富集，但在AngII处理中未富集。 和 是PI3K-Akt通路的组成部分，但在对AngII和IGF-1的反应中具有不同的DNA甲基化模式。qRT-PCR证实了 和 的基因表达不同。我们的研究率先对成年人类心肌细胞在不同应激条件下（病理性（AngII）和生理性（IGF-1））的表观基因组DNA甲基化变化进行了分析。所识别的DNA甲基化位点、基因和通路可能有潜力区分病理性和生理性心脏肥大。
