RATIONALE:Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the early morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood.OBJECTIVE:The objectives are to investigate the recruitment of transcription factors to time-of-day differentially accessible chromatin that underpins day-night ion channel rhythms and to assess the significance of this for the heart’s day-night rhythm in VA susceptibility.METHODS AND RESULTS:Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the inactive (zeitgeber time, time of lights on, start of sleep period) and active (time of lights off, start of awake period [ZT12]) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) binding site in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na⁺ current, Kcnh2 underlying the rapid delayed rectifier K⁺ current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts.CONCLUSIONS:Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.

中文翻译：

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心脏 GR 介导室性心律失常易感性的昼夜节律

理由：室性心律失常（VA）表现出明显的昼夜节律，通常出现在清晨。心脏离子通道中的转录节律伴随着这种现象，但它们在早晨易受 VAs 影响的过程中所起的作用以及潜在的机制尚不清楚。 目的：目的是研究转录因子招募到一天中不同时间的可差异性染色质的情况，这些染色质是支撑的基础昼夜离子通道节律，并评估其对心脏昼夜节律在 VA 敏感性中的重要性。方法和结果：在非活动（zeitgeber）开始时对小鼠心室肌细胞核进行测序，测定转座酶可及的染色质。时间、开灯时间、睡眠期开始）和活跃期（关灯时间、清醒期开始[ZT12]）时期揭示了可访问的染色质位点的差异，这些位点注释了这些区域中节律性转录的离子通道和转录因子结合基序。值得注意的是，在 ZT12 的开放染色质谱中观察到糖皮质激素受体（GR；皮质类固醇信号传导的转录效应器）结合位点的基序富集，与循环皮质类固醇中公认的 ZT12 峰一致。分子、电生理学和计算机生物物理详细建模方法证明了 GR 介导的离子通道转录控制（包括心脏 Na ^+电流的Scn5a、快速延迟整流器 K ^+电流的Kcnh2和负责电耦合的Gja1 ）及其贡献昼夜节律易受 VA 影响。引人注目的是，GR 的药理学阻断和 GR 的心肌细胞特异性基因敲除都会减弱或消除离子通道表达节律，并消除离体心脏中 ZT12 对起搏诱导的 VA 的敏感性。结论：我们的研究记录了染色质可及性的昼夜节律，伴随心室肌细胞的昼夜周期。我们的方法直接将心脏 GR 与心肌细胞兴奋性节律相关，并在机制上将糖皮质激素中的 ZT12 激增与此时的内在 VA 倾向联系起来。