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Gene Expression Analyses during Spontaneous Reversal of Cardiomyopathy in Mice with Repressed Nuclear CUG-BP, Elav-Like Family (CELF) Activity in Heart Muscle.

Dasgupta T, Coram RJ, Stillwagon SJ, Ladd AN - PLoS ONE (2015)

Bottom Line: To the best of our knowledge, this was the first example of a genetically induced cardiomyopathy that spontaneously recovers without intervention.We found that differences in gene expression between the mild line and wild type hearts are greatly reduced in older animals, including a partial recovery of SRF target gene expression.We did not find evidence of a new compensatory pathway being activated in the mild line with age, and propose that recovery may occur due to developmental stage-specific compatibility of CELF-dependent splice variants with the cellular environment of the cardiomyocyte.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

ABSTRACT
CUG-BP, Elav-like family (CELF) proteins regulate cell type- and developmental stage-specific alternative splicing in the heart. Repression of CELF-mediated splicing activity via expression of a nuclear dominant negative CELF protein in heart muscle was previously shown to induce dysregulation of alternative splicing, cardiac dysfunction, cardiac hypertrophy, and dilated cardiomyopathy in MHC-CELFΔ transgenic mice. A "mild" line of MHC-CELFΔ mice that expresses a lower level of the dominant negative protein exhibits cardiac dysfunction and myopathy at a young age, but spontaneously recovers normal cardiac function and heart size with age despite the persistence of splicing defects. To the best of our knowledge, this was the first example of a genetically induced cardiomyopathy that spontaneously recovers without intervention. In this study, we explored the basis for this recovery. We examined whether a transcriptional program regulated by serum response factor (SRF) that is dysregulated in juvenile MHC-CELFΔ mice is restored in the mild line with age, and evaluated global changes in gene expression by microarray analyses. We found that differences in gene expression between the mild line and wild type hearts are greatly reduced in older animals, including a partial recovery of SRF target gene expression. We did not find evidence of a new compensatory pathway being activated in the mild line with age, and propose that recovery may occur due to developmental stage-specific compatibility of CELF-dependent splice variants with the cellular environment of the cardiomyocyte.

No MeSH data available.


Related in: MedlinePlus

The number of affected genes in mild and severe lines at 3 and 24 weeks.Venn diagrams show the respective overlap of affected genes in MHC-CELFΔ-574 (“mild”) or MHC-CELFΔ-10 (“severe”) lines at 3 versus 24 weeks as compared to wild type mice at the same age.
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pone.0124462.g003: The number of affected genes in mild and severe lines at 3 and 24 weeks.Venn diagrams show the respective overlap of affected genes in MHC-CELFΔ-574 (“mild”) or MHC-CELFΔ-10 (“severe”) lines at 3 versus 24 weeks as compared to wild type mice at the same age.

Mentions: To determine how global gene expression differences in MHC-CELFΔ mice change over time, we performed microarray analysis on total RNA extracted from wild type, MHC-CELFΔ mild and severe line hearts at 3 and 24 weeks of age. Wild type versus mild line and wild type versus severe line comparisons were made, and differentially expressed genes that exhibit an absolute fold change ≥ 2 were identified (S2 and S3 Tables, respectively). Differences at 3 weeks were then compared to differences at 24 weeks (Fig 3). Consistent with the reversal of cardiomyopathy, fewer genes differed from wild type in the mild line at 24 weeks than at 3 weeks. In fact, more genes returned to a normal level of expression than remained dysregulated. In the severe line where there is no functional recovery, however, global gene expression became more disrupted with age. For mild and severe lines, all of the genes that were dysregulated both at 3 weeks and 24 weeks showed changes in the same direction at the two ages, and most displayed a similar magnitude of change. This suggests that these sets of changes are not evoked as a consequence of either progressive degeneration (in the severe line) or compensation (in the mild line).


Gene Expression Analyses during Spontaneous Reversal of Cardiomyopathy in Mice with Repressed Nuclear CUG-BP, Elav-Like Family (CELF) Activity in Heart Muscle.

Dasgupta T, Coram RJ, Stillwagon SJ, Ladd AN - PLoS ONE (2015)

The number of affected genes in mild and severe lines at 3 and 24 weeks.Venn diagrams show the respective overlap of affected genes in MHC-CELFΔ-574 (“mild”) or MHC-CELFΔ-10 (“severe”) lines at 3 versus 24 weeks as compared to wild type mice at the same age.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4404138&req=5

pone.0124462.g003: The number of affected genes in mild and severe lines at 3 and 24 weeks.Venn diagrams show the respective overlap of affected genes in MHC-CELFΔ-574 (“mild”) or MHC-CELFΔ-10 (“severe”) lines at 3 versus 24 weeks as compared to wild type mice at the same age.
Mentions: To determine how global gene expression differences in MHC-CELFΔ mice change over time, we performed microarray analysis on total RNA extracted from wild type, MHC-CELFΔ mild and severe line hearts at 3 and 24 weeks of age. Wild type versus mild line and wild type versus severe line comparisons were made, and differentially expressed genes that exhibit an absolute fold change ≥ 2 were identified (S2 and S3 Tables, respectively). Differences at 3 weeks were then compared to differences at 24 weeks (Fig 3). Consistent with the reversal of cardiomyopathy, fewer genes differed from wild type in the mild line at 24 weeks than at 3 weeks. In fact, more genes returned to a normal level of expression than remained dysregulated. In the severe line where there is no functional recovery, however, global gene expression became more disrupted with age. For mild and severe lines, all of the genes that were dysregulated both at 3 weeks and 24 weeks showed changes in the same direction at the two ages, and most displayed a similar magnitude of change. This suggests that these sets of changes are not evoked as a consequence of either progressive degeneration (in the severe line) or compensation (in the mild line).

Bottom Line: To the best of our knowledge, this was the first example of a genetically induced cardiomyopathy that spontaneously recovers without intervention.We found that differences in gene expression between the mild line and wild type hearts are greatly reduced in older animals, including a partial recovery of SRF target gene expression.We did not find evidence of a new compensatory pathway being activated in the mild line with age, and propose that recovery may occur due to developmental stage-specific compatibility of CELF-dependent splice variants with the cellular environment of the cardiomyocyte.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

ABSTRACT
CUG-BP, Elav-like family (CELF) proteins regulate cell type- and developmental stage-specific alternative splicing in the heart. Repression of CELF-mediated splicing activity via expression of a nuclear dominant negative CELF protein in heart muscle was previously shown to induce dysregulation of alternative splicing, cardiac dysfunction, cardiac hypertrophy, and dilated cardiomyopathy in MHC-CELFΔ transgenic mice. A "mild" line of MHC-CELFΔ mice that expresses a lower level of the dominant negative protein exhibits cardiac dysfunction and myopathy at a young age, but spontaneously recovers normal cardiac function and heart size with age despite the persistence of splicing defects. To the best of our knowledge, this was the first example of a genetically induced cardiomyopathy that spontaneously recovers without intervention. In this study, we explored the basis for this recovery. We examined whether a transcriptional program regulated by serum response factor (SRF) that is dysregulated in juvenile MHC-CELFΔ mice is restored in the mild line with age, and evaluated global changes in gene expression by microarray analyses. We found that differences in gene expression between the mild line and wild type hearts are greatly reduced in older animals, including a partial recovery of SRF target gene expression. We did not find evidence of a new compensatory pathway being activated in the mild line with age, and propose that recovery may occur due to developmental stage-specific compatibility of CELF-dependent splice variants with the cellular environment of the cardiomyocyte.

No MeSH data available.


Related in: MedlinePlus