Department of Physiology & Cell Biology, Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, IL, USA.
J Mol Cell Cardiol. 2021 Feb;151:46-55. doi: 10.1016/j.yjmcc.2020.11.002. Epub 2020 Nov 12.
Regulation of gene expression plays a fundamental role in cardiac stress-responses. Modification of coding transcripts by adenosine methylation (mA) has recently emerged as a critical post-transcriptional mechanism underlying heart disease. Thousands of mammalian mRNAs are known to be mA-modified, suggesting that remodeling of the mA landscape may play an important role in cardiac pathophysiology. Here we found an increase in mA content in human heart failure samples. We then adopted genome-wide analysis to define all mA-regulated sites in human failing compared to non-failing hearts and identified targeted transcripts involved in histone modification as enriched in heart failure. Further, we compared all mA sites regulated in human hearts with the ones occurring in isolated rat hypertrophic cardiomyocytes to define cardiomyocyte-specific mA events conserved across species. Our results identified 38 shared transcripts targeted by mA during stress conditions, and 11 events that are unique to unstressed cardiomyocytes. Of these, further evaluation of select mRNA and protein abundances demonstrates the potential impact of mA on post-transcriptional regulation of gene expression in the heart.
基因表达调控在心脏应激反应中起着至关重要的作用。最近，腺苷甲基化（mA）对编码转录本的修饰已成为心脏病学中一种关键的转录后机制。已知数千种哺乳动物 mRNA 都受到 mA 的修饰，这表明 mA 图谱的重塑可能在心脏病理生理学中发挥重要作用。在这里，我们发现心力衰竭患者的样本中 mA 含量增加。然后，我们采用全基因组分析来确定与非衰竭心脏相比，人类衰竭心脏中所有受 mA 调控的位点，并鉴定出参与组蛋白修饰的靶向转录本在心力衰竭中富集。此外，我们将人类心脏中受调控的所有 mA 位点与分离的大鼠肥厚性心肌病细胞中的 mA 位点进行比较，以确定物种间保守的心肌细胞特异性 mA 事件。我们的研究结果确定了 38 个在应激条件下受 mA 靶向调控的共有转录本，以及 11 个在未受应激的心肌细胞中特有的事件。其中，对选定 mRNA 和蛋白丰度的进一步评估表明，mA 对心脏中基因表达的转录后调控具有潜在影响。
