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HCN4 gain-of-function mutation increases intrinsic heart rate and limits maladaptive remodeling under pressure overload

GSE329403 Mus musculus (mouse) RNA-seq (gene expression) 14 samples Submitted 2026/07/01 Platform GPL24247
At a glance

RNA-seq (gene expression) · mouse · 14 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Mus musculus (mouse)
Samples
14 samples: 4 × Sham.KI vs 4 × Sham.WT vs 4 × TAC.KI vs 2 × TAC.WTGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
HCN4 gain-of-function mutation increases intrinsic heart rate and limits maladaptive remodeling under pressure overloadFrontiers in pharmacology · 2026
Summary (written by the submitters)
Introduction: Gain-of-function (GOF) mutations in the cardiac pacemaker channel HCN4 have been associated with inappropriate sinus tachycardia in human patients. Chronic tachycardia is generally associated with adverse cardiac remodeling and cardiomyopathy, but whether enhanced HCN4 activity can induce or modulate such remodeling remains unknown.
Read the full summary ↓
We aimed to investigate the influence of an HCN4 gain-of-function mutation on cardiac function and structure under baseline and pressure overload conditions. Methods and Results: We generated HCN4(Y527F) knock-in mice (HCN4F) carrying a GOF mutation in the C-Linker of HCN4 channels, which shifts their activation curves to more positive potentials. Electrophysiological recordings confirmed increased channel availability at physiological membrane potentials. Telemetric ECGs and in vivo electrophysiological studies revealed an elevated mean and intrinsic heart rate, faster sinus node and atrioventricular conduction in HCN4F mice, but no spontaneous arrhythmias. In HCN4F mice, the heart rate histogram was truncated at lower heart rates, indicating fewer low-rate intervals and more frequent periods of elevated heart rate, while maximal heart rates remained comparable between the two phenotypes. Histological analysis did not reveal structural changes consistent with tachycardia-induced cardiomyopathy. Cardiac morphology, fibrosis, and contractility were indistinguishable between genotypes up to 12 months of age. Following transverse aortic constriction, both WT and HCN4F mice developed left ventricular hypertrophy, but HCN4F hearts exhibited less chamber dilatation, smaller left ventricular lumen, and preserved systolic function compared to WT. Gene expression and RNA-sequencing analyses revealed activation of a typical hypertrophic gene program in both genotypes, but distinct remodeling signatures. Discussion: The HCN4(Y527F) gain-of-function mutation increases intrinsic heart rate without inducing structural or functional deterioration. Under pressure overload, it even confers protection against maladaptive dilatation and contractile dysfunction. These findings challenge the concept that persistent inappropriately elevated heart rate is necessarily detrimental and suggest that enhanced HCN4 activity may facilitate adaptive cardiac responses to stress.
Published in
HCN4 gain-of-function mutation increases intrinsic heart rate and limits maladaptive remodeling under pressure overload
Hennis K, Rilling J, Pham L et al. · Frontiers in pharmacology 2026 · PMID 42358349 · doi:10.3389/fphar.2026.1840832
This dataset
Open GSE329403 in finder → Find more mouse RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE329403_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1458804 and SRA study SRP695734. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 42358349) ↗
Study design
4 × Sham.KI vs 4 × Sham.WT vs 4 × TAC.KI vs 2 × TAC.WT

Supports a between-group comparison across 14 samples.

How we read this: 4 replicated groups read from 14 sample titles; they account for 14 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
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