Author Correction: Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility

“…Figure 6C shows the mean hourly heart rate recorded over a ≈36-hour cycle from GR fl/fl mice and cardioGRKO mice. As expected, there was a distinct day-night rhythm in heart rate in GR fl/f mice, peaking at ZT12 at the onset of the dark/ active period, in line with previous observations made in wild-type mice by our laboratory 17,66 and others 19 (Figure 6C). However, this pattern was no longer discernible in cardioGRKO mice (Figure 6C).…”

“…ATAC-seq libraries were generated from myocyte nuclei isolated from adult male C57BL/6J mouse left ventricles harvested at the time of lights off, start of awake period (ZT12, active phase in nocturnal mice housed under standard light-dark conditions) and compared with nuclei isolated from the left ventricle collected at the time of lights on, start of sleep period (ZT0, the inactive phase in mice). The selection of these time points was based on previous work that identified increased intrinsic VA vulnerability at ZT12 versus ZT0 19 in mice, mirroring the early morning peak in the occurrence of VA and sudden cardiac death in humans. Pericentriolar Material 1 labeling 29 followed by fluorescent-activated cell sorting was applied to purify the myocyte nuclei fraction ( Supplemental Material ; Figure S1 ) from 2 biological duplicates per time point.…”

“…Strikingly, GR block blunted or abolished rhythmic expression in these transcripts (Figure 5D), consolidating the functionality of conserved GR motifs identified by our ATACseq studies (Figure 2E; Figure S4) and demonstrating that Scn5a and Kcnh2 are bona fide targets of GR. Intriguingly, the rhythmic transcript expression of Bmal1, the currently accepted driver of transcriptional rhythms in Scn5a and Kcnh2 12,16 and determinant of day-night VA susceptibility, 19 was unaffected by RU486 treatment (Figure 5D). These data, combined with in silico predictions (Figure 4F), prompted the hypothesis that suppression of ion channel rhythmicity with GR blockade will dampen the day-night rhythm in VA susceptibility.…”

“…We demonstrate that GR nuclear translocation and recruitment to precise and evolutionarily conserved open chromatin profiles in the biological morning determine a proarrhythmic electrophysiological substrate due, in part, to transcriptional control of 2 ion channels (SCN5A and KCNH2) and a gap junction protein (Connexin output cycles kaput (CLOCK) to activate gene expression, has been emphasized. Through mechanisms that are not fully understood, cardiomyocyte-specific knockout of Bmal1 has been reported to dampen day-night rhythms in the transcription of ion channels and Ca 2+ -handling molecules in the ventricles 12,16,19 and also reduce the density of I Na 12 and I Kr . 16 Although such loss-of-function studies in cardiomyocyte-specific circadian clock TF knockout mice have become a gold standard for demonstrating circadian control of cardiac electrical activity, studies in extra-cardiac tissues have revealed a complex regulatory mechanism in which clock TF-DNA binding is required but is not sufficient for transcriptional activation and that other factors, including favorable reorganization of chromatin structure, enhancer-enhancer interactions, and differential recruitment of nonclock TFs to tissue-specific accessible chromatin, play important roles.…”

“…Our predictions indicate that the wavelength is shorter at ZT12 (Figure 4F, right), and, therefore, the mouse heart will be able to sustain a reentrant arrhythmia more effectively. It is concluded that the increased vulnerability to VA at ZT12 19 Having identified a potential mechanism by which a daynight rhythm in Scn5a and Kcnh2 expression can contribute to increased intrinsic ZT12 VA susceptibility, we directly assessed GR involvement in this process. We conducted experiments using the well-characterized competitive GR antagonist RU486, which binds with high affinity (dissociation constant ≤10 −9 M) to the GR (and the progesterone receptor).…”