Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators
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ABSTRACT:
PROVIDER: PRJNA992438 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR25204667_1.fastq.gz | Fastqsanger.gz | |||
| SRR25204667_2.fastq.gz | Fastqsanger.gz | |||
| SRR25204668_1.fastq.gz | Fastqsanger.gz | |||
| SRR25204668_2.fastq.gz | Fastqsanger.gz | |||
| SRR25204669_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutation of the PRDM16 gene causes human dilated and noncompaction cardiomyopathy. The PRDM16 protein is a transcriptional regulator that affects cardiac development via Tbx5 and Hand1, thus regulating myocardial structure. The biallelic inactivation of Prdm16 induces severe cardiac dysfunction with postnatal lethality and hypertrophy in mice. The early pathological events that occur upon Prdm16 inactivation have not been explored. This study performed in-depth pathophysiological and molecular analyses of male and female Prdm16csp1/wt mice that carry systemic, monoallelic Prdm16 gene inactivation. We systematically assessed early molecular changes through transcriptomics, proteomics, and metabolomics. Kinetic modelling of cardiac metabolism was performed in silico with CARDIOKIN.
2023-07-21 | PXD043601 | Pride
Project description:Background: Mutation of the PRDM16 gene causes human dilated and noncompaction cardiomyopathy. The PRDM16 protein is a transcriptional regulator that affects cardiac development via Tbx5 and Hand1, thus regulating myocardial structure. The biallelic inactivation of Prdm16 induces severe cardiac dysfunction with postnatal lethality and hypertrophy in mice. The early pathological events that occur upon Prdm16 inactivation have not been explored. Methods: This study performed in-depth pathophysiological and molecular analyses of male and female Prdm16csp1/wt mice that carry systemic, monoallelic Prdm16 gene inactivation. We systematically assessed early molecular changes through transcriptomics, proteomics, and metabolomics. Kinetic modelling of cardiac metabolism was performed in silico with CARDIOKIN. Results: Prdm16csp1/wt mice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice. Prdm16csp1/wt cardiac tissue of both sexes showed reductions in metabolites associated with amino acid as well as glycerol metabolism, glycolysis, and the tricarboxylic acid cycle. Prdm16csp1/wt cardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively. An accumulation of triacylglycerides exclusively in male Prdm16csp1/wt hearts, suggests a sex-specific metabolic adaptation. Metabolic modelling using CARDIOKIN identified a reduction in fatty acid utilization in males as well as lower glucose utilization in female Prdm16csp1/wt cardiac tissue. On the level of transcripts and protein expression, Prdm16csp1/wt hearts demonstrate an upregulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre B-cell leukemia transcription factor interacting protein 1 (Pbxip1). The strongest concordant transcriptional upregulation was detected for Prdm16 itself, probably through an autoregulatory mechanism. Conclusions: Monoallelic, global Prdm16 mutation diminishes cardiac performance in Prdm16csp1/wt mice. Metabolic alterations and transcriptional dysregulation in Prdm16csp1/wt affect cardiac tissue. Female Prdm16csp1/wt mice develop a more pronounced phenotype, indicating sexual dimorphism at this early pathological window. This study suggests that metabolic dysregulation is an early event in the PRDM16 associated cardiac pathology.
2023-07-12 | GSE236791 | GEO
Project description:AimsMutation of the PRDM16 gene causes human dilated and non-compaction cardiomyopathy. The PRDM16 protein is a transcriptional regulator that affects cardiac development via Tbx5 and Hand1, thus regulating myocardial structure. The biallelic inactivation of Prdm16 induces severe cardiac dysfunction with post-natal lethality and hypertrophy in mice. The early pathological events that occur upon Prdm16 inactivation have not been explored.Methods and resultsThis study performed in-depth pathophysiological and molecular analyses of male and female Prdm16csp1/wt mice that carry systemic, monoallelic Prdm16 gene inactivation. We systematically assessed early molecular changes through transcriptomics, proteomics, and metabolomics. Kinetic modelling of cardiac metabolism was performed in silico with CARDIOKIN. Prdm16csp1/wt mice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice. Prdm16csp1/wt cardiac tissue of both sexes showed reductions in metabolites associated with amino acid as well as glycerol metabolism, glycolysis, and the tricarboxylic acid cycle. Prdm16csp1/wt cardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively. An accumulation of triacylglycerides exclusively in male Prdm16csp1/wt hearts suggests a sex-specific metabolic adaptation. Metabolic modelling using CARDIOKIN identified a reduction in fatty acid utilization in males as well as lower glucose utilization in female Prdm16csp1/wt cardiac tissue. On the level of transcripts and protein expression, Prdm16csp1/wt hearts demonstrate an up-regulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre-B-cell leukaemia transcription factor interacting protein 1 (Pbxip1). The strongest concordant transcriptional up-regulation was detected for Prdm16 itself, probably through an autoregulatory mechanism.ConclusionsMonoallelic, global Prdm16 mutation diminishes cardiac performance in Prdm16csp1/wt mice. Metabolic alterations and transcriptional dysregulation in Prdm16csp1/wt affect cardiac tissue. Female Prdm16csp1/wt mice develop a more pronounced phenotype, indicating sexual dimorphism at this early pathological window. This study suggests that metabolic dysregulation is an early event in the PRDM16 associated cardiac pathology.
| S-EPMC10874277 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) is one of the most frequent inherited heart condition and a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to increased workload caused by physiological or pathological stress, prolonged hypertrophy can lead to heart failure characterized by impaired systolic function, increased apoptosis, fibrosis, ventricular dilation, and impaired metabolic substrate flexibility. While the key regulators for cardiac hypertrophy are well studied, the role of Prdm16 in this process remains poorly understood. In the present study, we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N- methyltransferase factors (Ehmts) act together to reduce the expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of pro- hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Collectively, our results demonstrate that Prdm16 protects the heart against age-dependent cardiac hypertrophy, fibrosis, mitochondrial dysfunction, adverse metabolic remodeling, and heart failure.
2020-09-21 | GSE153988 | GEO
Project description:Loss of the PR domain 16 (PRDM16) genetic locus has been suggested as the needed trigger for the development of left ventricular non-compaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM) in patients with 1p36 deletion syndrome. Furthermore, lack of Prdm16 in the murine heart has recently been shown to cause a spectrum of cardiomyopathy phenotypes. In spite of these advances, our understanding of the downstream transcriptional pathways regulated by PRDM16 that lead to these cardiac phenotypes is limited. OBJECTIVE: to unveil the downstream transcriptional pathways involved in the development of cardiomyopathy phenotypes associated with PRDM16 mutations/deletion in human and mice. METHODS AND RESULTS: We hypothesized that PRDM16 acts as an upstream regulator of key transcriptional pathways involved in cardiac maturation. Induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with a PRDM16 variant, cardiac tissue from mice expressing the human variant, mice with cardiac-specific deletion of Prdm16 and in vitro gain and loss of Prdm16 function were employed. Here we show that de novo pathogenic variants in PRDM16 are sufficient to cause LVNC in humans. In contrast, haploinsufficiency or complete deletion of Prdm16 in cardiomyocytes in mice led to pathological hypertrophy and dilated cardiomyopathy respectively. We demonstrated that PRDM16 regulates cardiac maturation through the maintenance of estrogen-related receptors (ERRs) expression. By contrast, PRDM16 acts as a supressor of transforming growth factor beta (TGFB) signaling. CONCLUSIONS: PRDM16 is a novel regulator of cardiac maturation acting upstream of ERRs and their regulators, and a suppressor of fibrotic signaling including TGFB.
2023-12-01 | GSE193877 | GEO
Project description:Loss of the PR domain 16 (PRDM16) genetic locus has been suggested as the needed trigger for the development of left ventricular non-compaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM) in patients with 1p36 deletion syndrome. Furthermore, lack of Prdm16 in the murine heart has recently been shown to cause a spectrum of cardiomyopathy phenotypes. In spite of these advances, our understanding of the downstream transcriptional pathways regulated by PRDM16 that lead to these cardiac phenotypes is limited. OBJECTIVE: to unveil the downstream transcriptional pathways involved in the development of cardiomyopathy phenotypes associated with PRDM16 mutations/deletion in human and mice. METHODS AND RESULTS: We hypothesized that PRDM16 acts as an upstream regulator of key transcriptional pathways involved in cardiac maturation. Induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with a PRDM16 variant, cardiac tissue from mice expressing the human variant, mice with cardiac-specific deletion of Prdm16 and in vitro gain and loss of Prdm16 function were employed. Here we show that de novo pathogenic variants in PRDM16 are sufficient to cause LVNC in humans. In contrast, haploinsufficiency or complete deletion of Prdm16 in cardiomyocytes in mice led to pathological hypertrophy and dilated cardiomyopathy respectively. We demonstrated that PRDM16 regulates cardiac maturation through the maintenance of estrogen-related receptors (ERRs) expression. By contrast, PRDM16 acts as a supressor of transforming growth factor beta (TGFB) signaling. CONCLUSIONS: PRDM16 is a novel regulator of cardiac maturation acting upstream of ERRs and their regulators, and a suppressor of fibrotic signaling including TGFB.
2023-12-01 | GSE193873 | GEO
Project description:PRDM16 is a transcription factor with histone methyltransferase activity expressed at the earliest stages of cardiac development. Pathogenic mutations in humans lead to cardiomyopathy, conduction abnormalities and heart failure. PRDM16 is specifically expressed in ventricular but not atrial cardiomyocytes and declines in expression postnatally. Since in other tissues PRDM16 is best known for its role in binary cell fate decisions, we hypothesized a similar decision-making function in cardiomyocytes. Here, we demonstrated that cardiomyocyte-specific deletion of Prdm16 during cardiac development results in contractile dysfunction and abnormal electrophysiology of the postnatal heart, resulting in premature death. By combined RNA+ATAC single-cell sequencing we found that PRDM16 favors ventricular working cardiomyocyte identity, by opposing the activity of master regulators of atrial and ventricular conduction fate. Myocardial loss of Prdm16 during development resulted in hyperplasia of the ventricular conduction system. Hence, PRDM16 plays an indispensable role during cardiac development by driving ventricular working cardiomyocyte identity.
2024-09-18 | GSE255382 | GEO
Project description:Gene expression profile from brown adipose tissues of Prdm16 knockout and wile type mice. Prdm16 is a transcription factor that regulates the thermogenic gene program in brown and beige adipocytes. However, whether Prdm16 is required for the development or physiological function of brown adipose tissue (BAT) in vivo has been unclear. By analyzing mice that selectively lacked Prdm16 in the brown adipose lineage, we found that Prdm16 was dispensable for embryonic BAT development. Brown adipose tissues were collected from Prdm16 knockout and wiletype mice with 4 biological replicates per condition. Experiment was done in two separate batch for 6-week-old and 11-month-old. Extracted RNA was hybridized to Agilent two-color arrays.
2014-04-09 | E-GEOD-55080 | biostudies-arrayexpress
Project description:Regulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). Previous studies by gene disruption during mouse embryonic development have shown that transcription factor gene Prdm16 is important for the generation/maintenance of fetal liver HSCs; however, the underlying mechanisms and the function of Prdm16 in adult HSCs remain unclear. To investigate the role of Prdm16 in adult HSCs, we generated a novel conditional knockout mouse model and deleted Prdm16 in adult mouse hematopoietic system using the interferon inducible Mx1-Cre. Our results show that deletion of Prdm16 leads to a gradual decline of adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment. Prdm16 deletion in the hematopoietic system following transplantation produced the same phenotype indicating that the defect is intrinsic to the HSCs. This HSC loss was also exacerbated by stress induced by 5-FU injections. Annexin V staining showed no difference in apoptosis between wild type and knockout HSCs. In contrast, BrdU analysis revealed that loss of Prdm16 significantly increases cycling of long-term HSCs (LT-HSCs) with majority of the cells found in the S to G2/M phase. Consistently, RNA-seq analysis of mouse LT- HSCs with and without Prdm16 deletion showed that Prdm16 loss induced a significant decrease in the expression of several known cell cycle regulators of HSCs, among which Cdkn1a and Egr1 were further identified as direct targets of Prdm16. Our results suggest that Prdm16 preserves the function of adult LT-HSCs by promoting their quiescence.
2021-11-22 | GSE154011 | GEO
Project description:Prdm16 is a transcription factor that drives a complete program of brown adipocyte differentiation, but the mechanism by which Prdm16 activates gene transcription remains unknown. Utilizing ChIP-seq teqhnique, we found that Prdm16 binds to chromatin at/near many brown fat-selective genes in BAT. Interestingly, Prdm16-deficiency dramatically reduced the binding of Med1 to Prdm16-target sites. Indeed, Prdm16 binds and recruits Med1 to BAT-enriched genes and the loss of Prdm16 caused a fundamental change in chromatin architecture at key BAT-selective genes and also reduced transcirptional activity. Moreover, Prdm16, through its interaction with Med1, defines and regulates the activity of super-enhancers that drive the expression of cell identity genes. Together, these data demonstrate that Prdm16 drives gene transcription by recruiting Med1 to control chromatin architecture and super-enhancers. Brown adipose tissues were collected from Prdm16 knockout and wiletype 9-month-old mice and ChIP-seq was performed for Prdm16, PolII, Med1, and H3K27ac.
2015-02-10 | E-GEOD-63965 | biostudies-arrayexpress