MBNL1 regulates programmed postnatal switching between regenerative and differentiated cardiac states [ActD RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1034549 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26627518_1.fastq.gz | Fastqsanger.gz | |||
| SRR26627518_2.fastq.gz | Fastqsanger.gz | |||
| SRR26627519_1.fastq.gz | Fastqsanger.gz | |||
| SRR26627519_2.fastq.gz | Fastqsanger.gz | |||
| SRR26627520_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246743 | GEO
Project description:MBNL1 regulates programmed postnatal switching between regenerative and differentiated cardiac states
| PRJNA1034538 | ENA
Project description:MBNL1 regulates programmed postnatal switching between regenerative and differentiated cardiac states [scRNA-seq]
| PRJNA1034543 | ENA
Project description:MBNL1 regulates programmed postnatal switching between regenerative and differentiated cardiac states [RIP-seq]
| PRJNA1034546 | ENA
Project description:MBNL1 regulates programmed postnatal switching between regenerative and differentiated cardiac states [RNA-seq]
| PRJNA1034545 | ENA
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246742 | GEO
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246741 | GEO
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246740 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-03-06 | GSE246744 | GEO
Project description:Dynamic fibroblast state transitions underlie the heart’s fibrotic response, raising the possibility that tactical control of these transitions could alter maladaptive fibrotic outcomes. Transcriptome maturation by Muscleblind-like 1 (MBNL1) has emerged as a driver of differentiated cell states. Indeed, MBNL1 expression is elevated in conjunction with profibrotic transcripts in lineage traced myofibroblasts and modeling this gain in function by fibroblast-specific overexpression of an MBNL1 transgene induced a myofibroblast transcriptional identity in healthy hearts and promoted maladaptive myocyte remodeling and scar maturation following injury. Both fibroblast-specific and myofibroblast-specific loss of MBNL1 limited scar production and maturation, which was ascribed to negligible myofibroblast activity. MBNL1 deletion drove expansion of all quiescent cardiac fibroblast states and promoted mesenchymal stem cell characteristics while forced MBNL1 expression restricted state diversity by transitioning most fibroblasts to the most mature myofibroblast identity. These data suggest MBNL1 is a post-transcriptional switch controlling quiescent to myofibroblast transitions during cardiac wound healing.
2022-01-20 | GSE193308 | GEO