Tbx5 maintains atrial identity by regulating an atrial enhancer network
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ABSTRACT:
PROVIDER: PRJNA924314 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23013209_1.fastq.gz | Fastqsanger.gz | |||
| SRR23013209_2.fastq.gz | Fastqsanger.gz | |||
| SRR23013210_1.fastq.gz | Fastqsanger.gz | |||
| SRR23013210_2.fastq.gz | Fastqsanger.gz | |||
| SRR23013211_1.fastq.gz | Fastqsanger.gz |
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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.
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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.
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Project description:Understanding how the atrial and ventricular chambers of the heart maintain their distinct identity is a prerequisite for treating chamber-specific diseases. Here, we selectively inactivated the transcription factor Tbx5 in the atrial working myocardium of the neonatal mouse heart to show that it is required to maintain atrial identity. Atrial Tbx5 inactivation downregulated highly chamber specific genes such as Myl7 and Nppa, and increased expression of ventricular identity genes including Myl2. Using combined single nucleus transcriptome and open chromatin profiling, we assessed genomic accessibility changes underlying the altered atrial identity expression program, identifying 1846 genomic loci with greater accessibility in control atrial cardiomyocytes compared to KO aCMs. 69% of the control-enriched ATAC regions were bound by TBX5, demonstrating a role for TBX5 in maintaining genomic accessibility. These regions were associated with genes that had higher expression in control aCMs compared to KO aCMs, suggesting they act as TBX5-dependent enhancers. To confirm this hypothesis we analyzed chromatin looping of enhancers marked by H3K27Ac using HiChIP and found 510 chromatin loops that were sensitive to TBX5 dosage. Of the loops enriched in control aCMs, 73.7% contained anchors in control-enriched ATAC regions. Conversely, Tbx5 overexpression in the ventricular myocardium drove atrial gene expression. Together, these data demonstrate a role for TBX5 in maintaining the atrial gene expression program by binding to atrial enhancers to preserve tissue-specific chromatin architecture. We highlight this phenomenon at major atrial identity genes including Nppa, Bmp10 and Myl7. HiChIP for H3K27Ac from atria of TBX5KO and control animals
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Project description:Understanding how the atrial and ventricular chambers of the heart maintain their distinct identity is a prerequisite for treating chamber-specific diseases. Here, we selectively inactivated the transcription factor Tbx5 in the atrial working myocardium of the neonatal mouse heart to show that it is required to maintain atrial identity. Atrial Tbx5 inactivation downregulated highly chamber specific genes such as Myl7 and Nppa, and increased expression of ventricular identity genes including Myl2. Using combined single nucleus transcriptome and open chromatin profiling, we assessed genomic accessibility changes underlying the altered atrial identity expression program, identifying 1846 genomic loci with greater accessibility in control atrial cardiomyocytes compared to KO aCMs. 69% of the control-enriched ATAC regions were bound by TBX5, demonstrating a role for TBX5 in maintaining genomic accessibility. These regions were associated with genes that had higher expression in control aCMs compared to KO aCMs, suggesting they act as TBX5-dependent enhancers. To confirm this hypothesis we analyzed chromatin looping of enhancers marked by H3K27Ac using HiChIP and found 510 chromatin loops that were sensitive to TBX5 dosage. Of the loops enriched in control aCMs, 73.7% contained anchors in control-enriched ATAC regions. Conversely, Tbx5 overexpression in the ventricular myocardium drove atrial gene expression. Together, these data demonstrate a role for TBX5 in maintaining the atrial gene expression program by binding to atrial enhancers to preserve tissue-specific chromatin architecture. We highlight this phenomenon at major atrial identity genes including Nppa, Bmp10 and Myl7.
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