Quantitative proteomic and single-nucleus transcriptomics map of the sinus node elucidates the foundation of cardiac pacemaking
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ABSTRACT:
PROVIDER: PRJNA541019 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9008740.fastq.gz | Fastqsanger.gz | |||
| SRR9008750.fastq.gz | Fastqsanger.gz | |||
| SRR9008741.fastq.gz | Fastqsanger.gz | |||
| SRR9008732.fastq.gz | Fastqsanger.gz | |||
| SRR9008742.fastq.gz | Fastqsanger.gz |
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Project description:The sinus node is a collection of highly specialised cells constituting the heart’s pacemaker. It is keenly debated whether the so-called membrane or alternatively Ca2+ clocks provide the molecular substrate of pacemaking. By high-resolution mass spectrometry, we quantified >7,000 proteins from sinus node and neighbouring atrial muscle. The abundances of 575 proteins differed between the two tissues, including particular differences in metabolic profiles and extracellular matrix composition. Most notably, the data reveal significant differences between the tissues in the ion channels responsible for the membrane clock, but not in Ca2+ clock proteins, suggesting that the membrane clock underpins pacemaking. By performing single-nucleus RNA sequencing of sinus node biopsies, we attributed protein abundances to specific cell types. Consistent with these results, incorporation of the ion channel expression differences into a biophysically-detailed atrial action potential model resulted in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the pacemaker of the heart.
2019-05-04 | GSE130710 | GEO
Project description:The sinus node is a collection of highly specialized cells that constitute the natural pacemaker activity of our heart. The protein expression landscape of the sinus node differs from the surrounding cardiac tissue, although it is primarily comprised of myocytes and fibroblasts like the rest of the cardiac tissue, endowing it with its unique ability to regulate heart rate. Here we performed quantitative proteomics experiments to profile protein expression in the pacemaker of the heart, and compared it to protein expression in the neighbouring atrial muscle. In summary, the quantitative proteomics data presented here offer a highly detailed insight into the unique composition of the pacemaker of our heart.
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Project description:In patients with heart failure, concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Here, we acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics and pharmacovigilance data highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in-vivo suppression of galectin-3 in the animal model of heart failure prevented SND. Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.
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Project description:Reduced spatiotemporal transcription factor levels have been shown to affect traits, organism development and disease predisposition. Here, we investigated the impact of physiologically relevant increases in transcription factor dosage, which has remained largely unexplored. Patients with genomic deletions far upstream of PITX2 present with sinus node dysfunction (SND) and atrial fibrillation. We show that delB mice, which recapitulate the deletion-driven arrhythmia in patients, ectopically express PITX2 in sinus node pacemaker cardiomyocytes (PCs) in a highly heterogeneous pattern from early embryonic development onwards. During development, delB sinus nodes form subdomains of mildly affected PC and strongly affected PCs that have lost their PC identity and switched towards an atrial cardiomyocyte-like state in a PITX2 dosage-dependent manner. Compared to heterozygous delB mice, homozygous delB mice have more PITX2+ PCs that express on average more PITX2, form proportionally larger subdomains of strongly affected PCs and have much more severe SND and atrial arrhythmia susceptibility. Ectopic expression of PITX2 in human induced pluripotent stem cell-derived PCs resulted in PITX2 dosage-dependent transcriptional changes reminiscent of those observed in the sinus node subdomains of delB mice. These results show that genetically driven ectopic expression of PITX2 in PCs causes SND and increased susceptibility for atrial arrhythmias, illustrating how spatiotemporally-defined increases in transcription factor dosage translates into developmental defects and disease predisposition.
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Project description:Reduced spatiotemporal transcription factor levels have been shown to affect traits, organism development and disease predisposition. Here, we investigated the impact of physiologically relevant increases in transcription factor dosage, which has remained largely unexplored. Patients with genomic deletions far upstream of PITX2 present with sinus node dysfunction (SND) and atrial fibrillation. We show that delB mice, which recapitulate the deletion-driven arrhythmia in patients, ectopically express PITX2 in sinus node pacemaker cardiomyocytes (PCs) in a highly heterogeneous pattern from early embryonic development onwards. During development, delB sinus nodes form subdomains of mildly affected PC and strongly affected PCs that have lost their PC identity and switched towards an atrial cardiomyocyte-like state in a PITX2 dosage-dependent manner. Compared to heterozygous delB mice, homozygous delB mice have more PITX2+ PCs that express on average more PITX2, form proportionally larger subdomains of strongly affected PCs and have much more severe SND and atrial arrhythmia susceptibility. Ectopic expression of PITX2 in human induced pluripotent stem cell-derived PCs resulted in PITX2 dosage-dependent transcriptional changes reminiscent of those observed in the sinus node subdomains of delB mice. These results show that genetically driven ectopic expression of PITX2 in PCs causes SND and increased susceptibility for atrial arrhythmias, illustrating how spatiotemporally-defined increases in transcription factor dosage translates into developmental defects and disease predisposition.
2025-11-11 | GSE291752 | GEO
Project description:Reduced spatiotemporal transcription factor levels have been shown to affect traits, organism development and disease predisposition. Here, we investigated the impact of physiologically relevant increases in transcription factor dosage, which has remained largely unexplored. Patients with genomic deletions far upstream of PITX2 present with sinus node dysfunction (SND) and atrial fibrillation. We show that delB mice, which recapitulate the deletion-driven arrhythmia in patients, ectopically express PITX2 in sinus node pacemaker cardiomyocytes (PCs) in a highly heterogeneous pattern from early embryonic development onwards. During development, delB sinus nodes form subdomains of mildly affected PC and strongly affected PCs that have lost their PC identity and switched towards an atrial cardiomyocyte-like state in a PITX2 dosage-dependent manner. Compared to heterozygous delB mice, homozygous delB mice have more PITX2+ PCs that express on average more PITX2, form proportionally larger subdomains of strongly affected PCs and have much more severe SND and atrial arrhythmia susceptibility. Ectopic expression of PITX2 in human induced pluripotent stem cell-derived PCs resulted in PITX2 dosage-dependent transcriptional changes reminiscent of those observed in the sinus node subdomains of delB mice. These results show that genetically driven ectopic expression of PITX2 in PCs causes SND and increased susceptibility for atrial arrhythmias, illustrating how spatiotemporally-defined increases in transcription factor dosage translates into developmental defects and disease predisposition.
2025-11-11 | GSE291749 | GEO
Project description:Reduced spatiotemporal transcription factor levels have been shown to affect traits, organism development and disease predisposition. Here, we investigated the impact of physiologically relevant increases in transcription factor dosage, which has remained largely unexplored. Patients with genomic deletions far upstream of PITX2 present with sinus node dysfunction (SND) and atrial fibrillation. We show that delB mice, which recapitulate the deletion-driven arrhythmia in patients, ectopically express PITX2 in sinus node pacemaker cardiomyocytes (PCs) in a highly heterogeneous pattern from early embryonic development onwards. During development, delB sinus nodes form subdomains of mildly affected PC and strongly affected PCs that have lost their PC identity and switched towards an atrial cardiomyocyte-like state in a PITX2 dosage-dependent manner. Compared to heterozygous delB mice, homozygous delB mice have more PITX2+ PCs that express on average more PITX2, form proportionally larger subdomains of strongly affected PCs and have much more severe SND and atrial arrhythmia susceptibility. Ectopic expression of PITX2 in human induced pluripotent stem cell-derived PCs resulted in PITX2 dosage-dependent transcriptional changes reminiscent of those observed in the sinus node subdomains of delB mice. These results show that genetically driven ectopic expression of PITX2 in PCs causes SND and increased susceptibility for atrial arrhythmias, illustrating how spatiotemporally-defined increases in transcription factor dosage translates into developmental defects and disease predisposition.
2025-11-11 | GSE291746 | GEO
Project description:The sinus node is a collection of highly specialised cells constituting the heart's pacemaker. The molecular underpinnings of its pacemaking abilities are debated. Using high-resolution mass spectrometry, we here quantify >7,000 proteins from sinus node and neighbouring atrial muscle. Abundances of 575 proteins differ between the two tissues. By performing single-nucleus RNA sequencing of sinus node biopsies, we attribute measured protein abundances to specific cell types. The data reveal significant differences in ion channels responsible for the membrane clock, but not in Ca2+ clock proteins, suggesting that the membrane clock underpins pacemaking. Consistently, incorporation of ion channel expression differences into a biophysically-detailed atrial action potential model result in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the cardiac pacemaker.
| S-EPMC6599035 | biostudies-literature