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TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [Tbx5_p.G125R]

ABSTRACT: snRNA-seq of Tbx5_p.G125R and control atrial nuclei

ORGANISM(S): Mus musculus

PROVIDER: GSE167357 | GEO | 2022/02/07

REPOSITORIES: GEO

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TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [CUT&RUN]

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

TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [ATAC-seq]

2022-02-07 | GSE166971 | GEO

TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [RNA-seq]

2022-02-07 | GSE166970 | GEO

TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-02-07 | GSE167082 | GEO

TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo

Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo

| PRJNA702928 | ENA

TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [Tbx5_p.G125R]

Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [Tbx5_p.G125R]

| PRJNA704371 | ENA

TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [CUT&RUN]

Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [CUT&RUN]

| PRJNA702934 | ENA

TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [RNA-seq]

Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [RNA-seq]

| PRJNA702494 | ENA

TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [ATAC-seq]

Project description:TBX5 G125R induces profound transcriptional deregulation and atrial dysfunction in vivo [ATAC-seq]

| PRJNA702496 | ENA

TBX5 Adult Knockout Left Atrial Gene Expression

Project description:TBX5 removed from adult mice with R26CreERt2, left and right atrial RNA extracted and sequenced.

2019-04-09 | GSE129503 | GEO

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