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Project description:BackgroundThe pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt-Oram syndrome (also known as hand-heart syndrome) and early onset of atrial fibrillation. Revealing how an altered key developmental transcription factor modulates cardiac physiology in vivo will provide unique insights into the mechanisms underlying atrial fibrillation in these patients.MethodsWe analyzed ECGs of an extended family pedigree of Holt-Oram syndrome patients. Next, we introduced the TBX5-p.G125R variant in the mouse genome (Tbx5G125R) and performed electrophysiologic analyses (ECG, optical mapping, patch clamp, intracellular calcium measurements), transcriptomics (single-nuclei and tissue RNA sequencing), and epigenetic profiling (assay for transposase-accessible chromatin using sequencing, H3K27ac [histone H3 lysine 27 acetylation] CUT&RUN [cleavage under targets and release under nuclease sequencing]).ResultsWe discovered high incidence of atrial extra systoles and atrioventricular conduction disturbances in Holt-Oram syndrome patients. Tbx5G125R/+ mice were morphologically unaffected and displayed variable RR intervals, atrial extra systoles, and susceptibility to atrial fibrillation, reminiscent of TBX5-p.G125R patients. Atrial conduction velocity was not affected but systolic and diastolic intracellular calcium concentrations were decreased and action potentials were prolonged in isolated cardiomyocytes of Tbx5G125R/+ mice compared with controls. Transcriptional profiling of atria revealed the most profound transcriptional changes in cardiomyocytes versus other cell types, and identified over a thousand coding and noncoding transcripts that were differentially expressed. Epigenetic profiling uncovered thousands of TBX5-p.G125R-sensitive, putative regulatory elements (including enhancers) that gained accessibility in atrial cardiomyocytes. The majority of sites with increased accessibility were occupied by Tbx5. The small group of sites with reduced accessibility was enriched for DNA-binding motifs of members of the SP (specificity protein) and KLF (Krüppel-like factor) families of transcription factors. These data show that Tbx5-p.G125R induces changes in regulatory element activity, alters transcriptional regulation, and changes cardiomyocyte behavior, possibly caused by altered DNA binding and cooperativity properties.ConclusionsOur data reveal that a disease-causing missense variant in TBX5 induces profound changes in the atrial transcriptional regulatory network and epigenetic state in vivo, leading to arrhythmia reminiscent of those seen in human TBX5-p.G125R variant carriers.
| S-EPMC8860223 | biostudies-literature
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
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:This SuperSeries is composed of the SubSeries listed below.
2022-02-07 | GSE167082 | GEO
Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo
| PRJNA702928 | ENA
Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [Tbx5_p.G125R]
| PRJNA704371 | ENA
Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [CUT&RUN]
| PRJNA702934 | ENA
Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [ATAC-seq]
| PRJNA702496 | ENA
Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [RNA-seq]
| PRJNA702494 | ENA