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| Status |
Public on Jul 06, 2023 |
| Title |
Arid1a is essential in cardiomyocytes for neonatal heart maturation [ChIP-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Adult mammalian hearts do not regenerate following ischemic injury, causing permanent damage to the myocardium, often leading to heart failure. In contrast, neonatal mouse hearts can fully regenerate after injury, however this ability is lost shortly after birth. Loss of regenerative capacity coincides with profound changes in the epigenetic landscape. Yet, the mechanisms controlling cardiomyocyte proliferation remain poorly understood. To identify epigenetic mechanisms that underlie cardiomyocyte regeneration in response to ischemic injury, we subjected mice to sham or ischemia-reperfusion injury (IR) and performed RNA-Seq at multiple timepoints after injury. Multiple SWI/SNF chromatin remodeling complex subunits were upregulated after IR, including the AT-rich interactive domain-containing protein 1A (Arid1a), which has previously been implicated in tissue regeneration. Here, we show that Arid1a is abundantly expressed in cardiomyocytes during development, and is reactivated in a subset of adult cardiomyocytes after IR. Moreover, ARID1A is highly expressed in cardiomyocytes in human failing hearts, suggesting an important function in injury response. Cardiomyocyte-specific Arid1a ablation in neonatal mice induced cardiomyocyte hyperplasia, and severe cardiac enlargement at 2 weeks of age. Arid1a mutant hearts display increased expression of key cell cycle genes. Using ChIP-Seq and protein interaction studies we show that Arid1a functionally interacts with HIPPO signaling, thereby regulating neonatal cardiomyocyte proliferation. Furthermore, suppression of Arid1a in adult cardiomyocytes after IR induced cell cycle activity in border zone cardiomyocytes. These data suggest that Arid1a regulates cardiomyocyte proliferation and function. Upregulation of Arid1a in cardiomyocytes after injury may suppress proliferation and regeneration. Modulation of ARID1A after ischemic injury may be a novel therapeutic target to enhance cardiac regeneration.
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| Overall design |
H3K27Ac ChIP-Seq on hearts of aMHC-Cre;Arid1a conditional mutant mice and control littermates
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| Web link |
https://doi.org/10.1038/s41467-023-40203-2
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| |
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| Contributor(s) |
Boogerd CJ |
| Citation(s) |
37543677 |
| |
| Submission date |
Jul 24, 2020 |
| Last update date |
Aug 14, 2023 |
| Contact name |
Cornelis J. Boogerd |
| E-mail(s) |
k.boogerd@hubrecht.eu
|
| Organization name |
Hubrecht Institute
|
| Department |
Developmental Biology and Stem Cell Research
|
| Street address |
Uppsalalaan 8
|
| City |
Utrecht |
| ZIP/Postal code |
3584CT |
| Country |
Netherlands |
| |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE155102 |
Arid1a is essential in cardiomyocytes for neonatal heart maturation |
|
| Relations |
| BioProject |
PRJNA648416 |
| SRA |
SRP273468 |
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