Transcriptome-wide profiling of thyroid hormone-dependent gene expression in the mouse heart
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE125596 | GEO | 2019/03/07
REPOSITORIES: GEO
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Project description:During the first weeks after birth, cardiomyocytes within the mouse heart progressively exit the cell cycle, binucleate, and lose regenerative capacity. We have determined that combined pharmacological inhibition of thyroid hormone and adrenergic signaling during postnatal development robustly enhances cardiomyocyte proliferation, retention of diploid cardiomyocytes, and functional cardiac regeneration at postnatal day 14. In this study, we perform transcriptome-wide analyses to understand the genetic pathways regulated by thyroid hormone, alpha-adreneric, and beta-adrenergic signaling - individually and in combination - that promote cardiomyocyte cell-cycle arrest and loss of cardiac regenerative potential.
2021-09-22 | GSE174511 | GEO
Project description:The mammalian heart is incapable of regenerating a sufficient number of cardiomyocytes to ameliorate the loss of contractile muscle after acute myocardial injury, often resulting in heart failure. Several reports have demonstrated that mononucleated (MoNuc) cardiomyocytes are more responsive to pro-proliferative stimuli than are binucleated (BiNuc) cardiomyocytes. However, techniques to isolate and characterize these two different cardiomyocyte populations have been lacking. We have developed a novel fluorescence associated cell sorting method to isolate highly enriched populations of MoNuc and BiNuc cardiomyocytes at various times of development. Transcriptome analysis reveals an underlying biological signature that defines the differences between MoNucs and BiNucs, including a central role for the E2f/Rb transcriptional network in establishing the divergent ability of these two populations to re-enter and complete the cell cycle. Moreover, inducing binucleation by genetically blocking the ability of cardiomyocytes to complete cytokinesis leads to a reduction in E2f target gene expression, linking the E2f pathway with nucleation. These data identify key molecular differences between MoNuc and BiNuc mammalian cardiomyocytes that can be used to leverage cardiomyocyte proliferation for promoting injury repair in the heart.
2020-02-26 | GSE140851 | GEO
Project description:The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart has a transient ability to regenerate, however the molecular mechanism that mediates this regenerative response is not fully understood. Here, by single-nucleus RNA sequencing we map the transcriptome landscape of cardiomyocytes in neonatal mouse hearts at healthy, regenerative, and remodeling conditions. We show that an immature cardiomyocyte population enters cell-cycle in response to injury. Absence of this cardiomyocyte population overtime is associated with the loss of the ability of the heart to regenerate. We show a defined injury response in these cardiomyocytes, including activation of transcription factors NFYa and NFE2L1, which play proliferative and protective roles, respectively. We further show that overexpression of these two factors in vivo promotes heart regeneration. Thus, these findings refined our understanding of cellular basis of neonatal heart regeneration and reveal dynamic transcriptome landscape of cardiomyocytes in response to injury.
2020-03-18 | GSE142365 | GEO
Project description:The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart has a transient ability to regenerate, however the molecular mechanism that mediates this regenerative response is not fully understood. Here, by single-nucleus RNA sequencing we map the transcriptome landscape of cardiomyocytes in neonatal mouse hearts at healthy, regenerative, and remodeling conditions. We show that an immature cardiomyocyte population enters cell-cycle in response to injury. Absence of this cardiomyocyte population overtime is associated with the loss of the ability of the heart to regenerate. We show a defined injury response in these cardiomyocytes, including activation of transcription factors NFYa and NFE2L1, which play proliferative and protective roles, respectively. We further show that overexpression of these two factors in vivo promotes heart regeneration. Thus, these findings refined our understanding of cellular basis of neonatal heart regeneration and reveal dynamic transcriptome landscape of cardiomyocytes in response to injury.
2020-03-18 | GSE142364 | GEO
Project description:Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline in geriatric satellite cells, compared to old cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a. Young Bmi1-deficient satellite cells shares similar features.
2013-12-31 | GSE53727 | GEO
Project description:The adult mammalian heart is incapable of regeneration following injury. In contrast, the neonatal mouse heart can efficiently regenerate during the first week of life. The molecular mechanisms that mediate the regenerative response and its blockade in later life are not understood. Here, by single-nucleus RNA sequencing, we map the dynamic transcriptional landscape of five distinct cardiomyocyte populations in healthy, injured and regenerating mouse hearts. We identify immature cardiomyocytes that enter the cell-cycle following injury and disappear as the heart loses the ability to regenerate. These proliferative neonatal cardiomyocytes display a unique transcriptional program dependent on NFYa and NFE2L1 transcription factors, which exert proliferative and protective functions, respectively. Cardiac overexpression of these two factors conferred protection against ischemic injury in mature mouse hearts that were otherwise non-regenerative. These findings advance our understanding of the cellular basis of neonatal heart regeneration and reveal a transcriptional landscape for heart repair following injury.
2020-03-18 | GSE130699 | GEO
Project description:Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline in geriatric satellite cells, compared to old cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a. Young Bmi1-deficient satellite cells shares similar features. We analyzed the global changes in gene expression occurring within muscle stem cells (satellite cells) in homeostatic conditions during physiological aging. Pure satellite cell populations from dissociated skeletal muscle from WT and Bmi1-deficient mice were isolated using a well-established flow cytometry protocol gating on integrin a7(+)/CD34(+) (positive selection) and Lin- (CD31, CD45, CD11b, Sca1) (negative selection).
2013-12-31 | E-GEOD-53727 | biostudies-arrayexpress
Project description:Background - The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we construct a transcriptional atlas of multiple cardiac cell populations, which enables comparative analyses of the regenerative (neonatal) versus non-regenerative (adult) state for the first time. Methods - Cardiomyocytes, fibroblasts, leukocytes and endothelial cells from infarcted and non-infarcted neonatal (P1) and adult (P56) hearts were isolated by enzymatic dissociation and FACS. RNA sequencing (RNA-seq) was performed on these cell populations to generate a transcriptomic atlas of the major cardiac cell populations during cardiac development, repair and regeneration. In addition, we surveyed the epigenetic landscape of cardiomyocytes during post-natal maturation by performing deep sequencing of accessible chromatin regions using the Assay for Transposase-Accessible Chromatin (ATAC-seq) from purified cardiomyocyte nuclei (P1, P14 and P56). Results - Profiling of cardiomyocyte and non-myocyte transcriptional programs uncovered several injury responsive genes across regenerative and non-regenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts reverted to a neonatal state and re-activated a neonatal proliferative network following infarction. In contrast, cardiomyocytes failed to re-activate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during post-natal maturation. Conclusions – This work provides a comprehensive transcriptional resource of multiple cardiac cell populations during cardiac development, repair and regeneration. Our findings define a transcriptional program underpinning the neonatal regenerative state and identifies an epigenetic barrier to re-induction of the regenerative program in adult cardiomyocytes.
2017-07-24 | GSE95763 | GEO
Project description:Background - The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we construct a transcriptional atlas of multiple cardiac cell populations, which enables comparative analyses of the regenerative (neonatal) versus non-regenerative (adult) state for the first time. Methods - Cardiomyocytes, fibroblasts, leukocytes and endothelial cells from infarcted and non-infarcted neonatal (P1) and adult (P56) hearts were isolated by enzymatic dissociation and FACS. RNA sequencing (RNA-seq) was performed on these cell populations to generate a transcriptomic atlas of the major cardiac cell populations during cardiac development, repair and regeneration. In addition, we surveyed the epigenetic landscape of cardiomyocytes during post-natal maturation by performing deep sequencing of accessible chromatin regions using the Assay for Transposase-Accessible Chromatin (ATAC-seq) from purified cardiomyocyte nuclei (P1, P14 and P56). Results - Profiling of cardiomyocyte and non-myocyte transcriptional programs uncovered several injury responsive genes across regenerative and non-regenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts reverted to a neonatal state and re-activated a neonatal proliferative network following infarction. In contrast, cardiomyocytes failed to re-activate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during post-natal maturation. Conclusions – This work provides a comprehensive transcriptional resource of multiple cardiac cell populations during cardiac development, repair and regeneration. Our findings define a transcriptional program underpinning the neonatal regenerative state and identifies an epigenetic barrier to re-induction of the regenerative program in adult cardiomyocytes.
2017-07-24 | GSE95762 | GEO
Project description:We reported the RNAseq analyses of right ventricualr free wall myocardium in young volume overload (VO) C57/BL6 mice.VO was induced by the fistula between abdominal aorta and inferior vena cava (AVF) on postnatal day 7(P7). RNAseq analyses of RV free wall at P14 and P21from VO and sham-operated mice revealed that there were 981 differentially expressed genes between VO and sham group at P14, this number increased to 1907 at P21, there were 3012 differentially expressed genes between P21 and P14 sham group, and the number increased to 3470 at the presence of VO. GO analysis showed that in the VO and sham comparison, the upregulated genes mainly mediated mitosis and cell division and the downregulated genes mainly mediated heart contraction at P14, and the upregulated genes mainly mediated immune response, and downregulated genes mainly mediated cellular respiration at P21. As expected, in the normal RV development during preadolescence (from P14 to P21), upregulated genes mainly mediated oxidative phosphorylation and cellular respiration and the downregulated genes mainly mediated vasculogenesis. VO changed the RV development, the upregulated genes mainly mediated heart contraction and the down regulated genes mainly mediated vasculogenesis and cell cycle. KEGG pathway analysis revealed that cell cycle pathway was upregulated and cardiac muscle contraction and thyroid hormone signaling pathway were downregulated between VO and sham group at P14, phagosome pathway was upregulated and citrate cycle (TCA) cycle and thermogenesis were downregulated at P21 between VO and sham group. In the normal RV development, TCA cycle and cardiac muscle contraction pathway were upregulated while VO changed that to the upregulations of cardiomyopathy pathways and thyroid hormone signaling pathway. All the above changes were further confirmed by the functional tests.
2021-08-16 | GSE157396 | GEO