Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Commun Biol. 2023 Nov 11;6(1):1149. doi: 10.1038/s42003-023-05537-z.
Circadian disruption increases cardiovascular disease (CVD) risk, through poorly understood mechanisms. Given that small RNA species are critical modulators of cardiac physiology/pathology, we sought to determine the extent to which cardiomyocyte circadian clock (CCC) disruption impacts cardiac small RNA species. Accordingly, we collected hearts from cardiomyocyte-specific Bmal1 knockout (CBK; a model of CCC disruption) and littermate control (CON) mice at multiple times of the day, followed by small RNA-seq. The data reveal 47 differentially expressed miRNAs species in CBK hearts. Subsequent bioinformatic analyses predict that differentially expressed miRNA species in CBK hearts influence processes such as circadian rhythmicity, cellular signaling, and metabolism. Of the induced miRNAs in CBK hearts, 7 are predicted to be targeted by the transcriptional repressors REV-ERBα/β (integral circadian clock components that are directly regulated by BMAL1). Similar to CBK hearts, cardiomyocyte-specific Rev-erbα/β double knockout (CM-RevDKO) mouse hearts exhibit increased let-7c-1-3p, miR-23b-5p, miR-139-3p, miR-5123, and miR-7068-3p levels. Importantly, 19 putative targets of these 5 miRNAs are commonly repressed in CBK and CM-RevDKO heart (of which 16 are targeted by let-7c-1-3p). These observations suggest that disruption of the circadian BMAL1-REV-ERBα/β regulatory network in the heart induces distinct miRNAs, whose mRNA targets impact critical cellular functions.
昼夜节律紊乱通过尚未完全阐明的机制增加心血管疾病 (CVD) 的风险。鉴于小 RNA 种类是心脏生理学/病理学的关键调节因子，我们试图确定心肌细胞昼夜节律钟 (CCC) 紊乱对心脏小 RNA 种类的影响程度。因此，我们在一天中的多个时间点从心肌细胞特异性 Bmal1 敲除 (CBK；CCC 破坏模型) 和同窝对照 (CON) 小鼠中收集心脏，然后进行小 RNA-seq。数据显示 CBK 心脏中有 47 种差异表达的 miRNA 种类。随后的生物信息学分析预测，CBK 心脏中差异表达的 miRNA 种类会影响昼夜节律性、细胞信号转导和代谢等过程。在 CBK 心脏中诱导的 miRNA 中，有 7 种被转录抑制因子 REV-ERBα/β (直接受 BMAL1 调节的完整昼夜节律钟成分) 靶向。与 CBK 心脏相似，心肌细胞特异性 Rev-erbα/β 双敲除 (CM-RevDKO) 小鼠心脏中 let-7c-1-3p、miR-23b-5p、miR-139-3p、miR-5123 和 miR-7068-3p 的水平增加。重要的是，这 5 种 miRNA 的 19 个假定靶基因在 CBK 和 CM-RevDKO 心脏中共同受到抑制 (其中 16 个被 let-7c-1-3p 靶向)。这些观察结果表明，心脏中昼夜节律紊乱的 BMAL1-REV-ERBα/β 调节网络的破坏会诱导不同的 miRNA，其 mRNA 靶标会影响关键的细胞功能。
