A reduced TBX5-dependent gene regulatory network links atrial fibrillation and heart failure [Micro-C]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE311699 | GEO | 2025/12/01
REPOSITORIES: GEO
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Project description:Atrial fibrillation (AF) and heart failure (HF) frequently co-occur and exacerbate each other's morbidity, yet the underlying molecular mechanisms remain incompletely understood. Here, we compared atrial gene regulatory networks across multiple mouse models of AF (Tbx5 cKO, Zfhx3 KO, Scn1b-null) and HF (TAC, AngII), revealing unexpected transcriptional and genomic convergence between Tbx5 cKO and HF models. Notably, Tbx5 was significantly downregulated in atrial tissue from both murine and human HF samples. We identified over 100 coordinately dysregulated Tbx5- and TAC-dependent transcription factor genes, with cell-type resolution achieved through single-cell transcriptomics. Loss of a TBX5-driven cardiomyocyte gene regulatory network—including Klf15, a transcriptional repressor of hypertrophy—was observed in both AF and HF models, while a shared disease-specific network emerged in activated fibroblasts, notably involving the pro-fibrotic regulator Sox9. These findings define a conserved TBX5-dependent atrial genomic injury response that may underlie the reciprocal pathophysiological relationship between AF and HF.
2025-11-30 | GSE311495 | GEO
Project description:Atrial fibrillation (AF) and heart failure (HF) frequently co-occur and exacerbate each other's morbidity, yet the underlying molecular mechanisms remain incompletely understood. Here, we compared atrial gene regulatory networks across multiple mouse models of AF (Tbx5 cKO, Zfhx3 KO, Scn1b-null) and HF (TAC, AngII), revealing unexpected transcriptional and genomic convergence between Tbx5 cKO and HF models. Notably, Tbx5 was significantly downregulated in atrial tissue from both murine and human HF samples. We identified over 100 coordinately dysregulated Tbx5- and TAC-dependent transcription factor genes, with cell-type resolution achieved through single-cell transcriptomics. Loss of a TBX5-driven cardiomyocyte gene regulatory network—including Klf15, a transcriptional repressor of hypertrophy—was observed in both AF and HF models, while a shared disease-specific network emerged in activated fibroblasts, notably involving the pro-fibrotic regulator Sox9. These findings define a conserved TBX5-dependent atrial genomic injury response that may underlie the reciprocal pathophysiological relationship between AF and HF.
2025-11-30 | GSE311492 | GEO
Project description:Background: ZFHX3, a gene that encodes a large transcription factor, is the second-most significantly associated locus with AF, but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, MRI, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 deletion (Zfhx3 Het and KO, respectively). Human cardiac single-nucleus ATAC-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. Results: We found SNP rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility withZfhx3KO mice having higher incidence, frequency, and burden of AF thanZfhx3Het and WT mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. Conclusions: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF-susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.
2023-06-30 | GSE229525 | GEO
Project description:Atrial fibrillation (AF), the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 is essential for normal atrial rhythm, and its inactivation causes loss of aCM enhancer accessibility, looping, and transcriptional identity, and causes spontaneous AF. Here we investigated mechanisms by which TBX5 regulates chromatin organization. We found that TBX5 recruits CHD4, a chromatin remodeling ATPase canonically associated with the NuRD repressor complex, to 33,170 genomic regions (TBX5-enhanced CHD4 sites). Combined snRNA-seq and snATAC-seq of CHD4 knockout (KO) and control aCMs revealed that CHD4 has both gene activator and repressor functions. CHD4-repressed genes included sarcomeric proteins from non-CM cell lineages. CHD4-activated genes were characterized by TBX5-enhanced CHD4 recruitment, which enhanced chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of TBX5 recruitment of CHD4 was critical for sinus rhythm because Chd4AKO mice had increased vulnerability to AF. Our findings reveal that CHD4 is essential for maintaining aCM gene expression, aCM identity, and atrial rhythm homeostasis.
2025-08-04 | GSE284094 | GEO
Project description:Atrial fibrillation (AF), the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 is essential for normal atrial rhythm, and its inactivation causes loss of aCM enhancer accessibility, looping, and transcriptional identity, and causes spontaneous AF. Here we investigated mechanisms by which TBX5 regulates chromatin organization. We found that TBX5 recruits CHD4, a chromatin remodeling ATPase canonically associated with the NuRD repressor complex, to 33,170 genomic regions (TBX5-enhanced CHD4 sites). Combined snRNA-seq and snATAC-seq of CHD4 knockout (KO) and control aCMs revealed that CHD4 has both gene activator and repressor functions. CHD4-repressed genes included sarcomeric proteins from non-CM cell lineages. CHD4-activated genes were characterized by TBX5-enhanced CHD4 recruitment, which enhanced chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of TBX5 recruitment of CHD4 was critical for sinus rhythm because Chd4AKO mice had increased vulnerability to AF. Our findings reveal that CHD4 is essential for maintaining aCM gene expression, aCM identity, and atrial rhythm homeostasis.
2025-08-04 | GSE284093 | GEO
Project description:Atrial fibrillation (AF), the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 is essential for normal atrial rhythm, and its inactivation causes loss of aCM enhancer accessibility, looping, and transcriptional identity, and causes spontaneous AF. Here we investigated mechanisms by which TBX5 regulates chromatin organization. We found that TBX5 recruits CHD4, a chromatin remodeling ATPase canonically associated with the NuRD repressor complex, to 33,170 genomic regions (TBX5-enhanced CHD4 sites). Combined snRNA-seq and snATAC-seq of CHD4 knockout (KO) and control aCMs revealed that CHD4 has both gene activator and repressor functions. CHD4-repressed genes included sarcomeric proteins from non-CM cell lineages. CHD4-activated genes were characterized by TBX5-enhanced CHD4 recruitment, which enhanced chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of TBX5 recruitment of CHD4 was critical for sinus rhythm because Chd4AKO mice had increased vulnerability to AF. Our findings reveal that CHD4 is essential for maintaining aCM gene expression, aCM identity, and atrial rhythm homeostasis.
2025-08-04 | GSE284095 | GEO
Project description:Atrial fibrillation (AF), the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 is essential for normal atrial rhythm, and its inactivation causes loss of aCM enhancer accessibility, looping, and transcriptional identity, and causes spontaneous AF. Here we investigated mechanisms by which TBX5 regulates chromatin organization. We found that TBX5 recruits CHD4, a chromatin remodeling ATPase canonically associated with the NuRD repressor complex, to 33,170 genomic regions (TBX5-enhanced CHD4 sites). Combined snRNA-seq and snATAC-seq of CHD4 knockout (KO) and control aCMs revealed that CHD4 has both gene activator and repressor functions. CHD4-repressed genes included sarcomeric proteins from non-CM cell lineages. CHD4-activated genes were characterized by TBX5-enhanced CHD4 recruitment, which enhanced chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of TBX5 recruitment of CHD4 was critical for sinus rhythm because Chd4AKO mice had increased vulnerability to AF. Our findings reveal that CHD4 is essential for maintaining aCM gene expression, aCM identity, and atrial rhythm homeostasis.
2025-08-04 | GSE296675 | GEO
Project description:Rationale: Pathogenic variants in the gene for T-box transcription factor (TF) 5 (TBX5) cause Holt-Oram syndrome (HOS), characterized by congenital heart defects and limb abnormalities. A particular missense variant in TBX5 (G125R) in a Dutch family causes atypical HOS as well as early onset atrial fibrillation (AF). Understanding the effects of such an altered key cardiac TF on the transcription regulatory network and cardiac physiology provides a unique opportunity to gain insight into the mechanisms underlying diseases such as AF. Objective: To determine the in vivo TBX5-G125R-induced changes in the transcriptional regulatory network and epigenetic state underlying the atypical HOS with early onset AF found in an extended pedigree. Methods and Results: We modeled the TBX5-G125R pathogenic variant in vivo in the mouse and found severe cardiac defects and fetal lethality in Tbx5G125R/G125R mice, whereas Tbx5G125R/+ mice were viable and morphologically unaffected. Electrophysiological analysis of adult Tbx5G125R/+ mice revealed variable RR interval, atrial extra systole and susceptibility to AF upon pacing. These characteristics were also observed in the patient family. Additionally, calcium homeostasis as well as conduction were changed in the mutant atrial cardiomyocytes. Single-nucleus transcriptional profiling of right atria revealed the most profound changes in expression in the cardiomyocytes of Tbx5G125R/+ mice. Transcriptional profiling of atrial tissue identified differential expression of over a thousand genes, whereas expression levels of several genes known to respond to Tbx5 insufficiency did not change. Epigenetic profiling revealed shifts in sites associated with acetylated H3K27 as well as in chrom atin accessibility in Tbx5G125R/+ atrial cardiomyocytes indicating Tbx5-G125R has altered DNA binding and TF interaction properties.
2022-02-07 | GSE166971 | GEO
Project description:Rationale: Pathogenic variants in the gene for T-box transcription factor (TF) 5 (TBX5) cause Holt-Oram syndrome (HOS), characterized by congenital heart defects and limb abnormalities. A particular missense variant in TBX5 (G125R) in a Dutch family causes atypical HOS as well as early onset atrial fibrillation (AF). Understanding the effects of such an altered key cardiac TF on the transcription regulatory network and cardiac physiology provides a unique opportunity to gain insight into the mechanisms underlying diseases such as AF. Objective: To determine the in vivo TBX5-G125R-induced changes in the transcriptional regulatory network and epigenetic state underlying the atypical HOS with early onset AF found in an extended pedigree. Methods and Results: We modeled the TBX5-G125R pathogenic variant in vivo in the mouse and found severe cardiac defects and fetal lethality in Tbx5G125R/G125R mice, whereas Tbx5G125R/+ mice were viable and morphologically unaffected. Electrophysiological analysis of adult Tbx5G125R/+ mice revealed variable RR interval, atrial extra systole and susceptibility to AF upon pacing. These characteristics were also observed in the patient family. Additionally, calcium homeostasis as well as conduction were changed in the mutant atrial cardiomyocytes. Single-nucleus transcriptional profiling of right atria revealed the most profound changes in expression in the cardiomyocytes of Tbx5G125R/+ mice. Transcriptional profiling of atrial tissue identified differential expression of over a thousand genes, whereas expression levels of several genes known to respond to Tbx5 insufficiency did not change. Epigenetic profiling revealed shifts in sites associated with acetylated H3K27 as well as in chrom atin accessibility in Tbx5G125R/+ atrial cardiomyocytes indicating Tbx5-G125R has altered DNA binding and TF interaction properties.
2022-02-07 | GSE166970 | GEO
Project description:Rationale: Pathogenic variants in the gene for T-box transcription factor (TF) 5 (TBX5) cause Holt-Oram syndrome (HOS), characterized by congenital heart defects and limb abnormalities. A particular missense variant in TBX5 (G125R) in a Dutch family causes atypical HOS as well as early onset atrial fibrillation (AF). Understanding the effects of such an altered key cardiac TF on the transcription regulatory network and cardiac physiology provides a unique opportunity to gain insight into the mechanisms underlying diseases such as AF. Objective: To determine the in vivo TBX5-G125R-induced changes in the transcriptional regulatory network and epigenetic state underlying the atypical HOS with early onset AF found in an extended pedigree. Methods and Results: We modeled the TBX5-G125R pathogenic variant in vivo in the mouse and found severe cardiac defects and fetal lethality in Tbx5G125R/G125R mice, whereas Tbx5G125R/+ mice were viable and morphologically unaffected. Electrophysiological analysis of adult Tbx5G125R/+ mice revealed variable RR interval, atrial extra systole and susceptibility to AF upon pacing. These characteristics were also observed in the patient family. Additionally, calcium homeostasis as well as conduction were changed in the mutant atrial cardiomyocytes. Single-nucleus transcriptional profiling of right atria revealed the most profound changes in expression in the cardiomyocytes of Tbx5G125R/+ mice. Transcriptional profiling of atrial tissue identified differential expression of over a thousand genes, whereas expression levels of several genes known to respond to Tbx5 insufficiency did not change. Epigenetic profiling revealed shifts in sites associated with acetylated H3K27 as well as in chrom atin accessibility in Tbx5G125R/+ atrial cardiomyocytes indicating Tbx5-G125R has altered DNA binding and TF interaction properties.
2022-02-07 | GSE167081 | GEO