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Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans and mice

ABSTRACT: Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans and mice

PROVIDER: PRJNA798271 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17652720.fastq.gz	Fastqsanger.gz
	SRR17652721.fastq.gz	Fastqsanger.gz
	SRR17652722.fastq.gz	Fastqsanger.gz
	SRR17652723.fastq.gz	Fastqsanger.gz
	SRR17652724.fastq.gz	Fastqsanger.gz

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Similar Datasets

Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans

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

Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in mice

2023-12-01 | GSE193873 | GEO

Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans

Project description:Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans

| PRJNA798273 | ENA

Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in mice

Project description:Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in mice

| PRJNA798263 | ENA

Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans and mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-01 | GSE193878 | GEO

Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators

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

Prdm16 Knockout Brown Adipose Tissue

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

PRDM16 is required for proper specification of the working ventricular myocardium by suppressing alternative cardiomyocyte cell fates.

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

Cistromic and epigenomic changes in Prdm16 knock-out brown adipose tissue

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

mRNA expression of murine hematopoietic stem cells and ex vivo murine MLL-AF9 cells deficient for total PRDM16 or f-PRDM16, and AF9 cells overexpressing individual PRDM16 isoforms

Project description:Group 1 -- WT or PRDM16-KO ex vivo murine MLL-AF9 cells, and PRDM16-KO AF9 cells overexpressing either f-PRDM16 or s-PRDM16. Group 2 -- WT or total PRDM16-KO murine HSCs isolated from adult BM. Group 3 -- WT or total PRDM16-KO murine HSCs isolated from fetal liver. Group 4 -- WT or f-PRDM16-KO murine HSCs (expressing s-PRDM16 only) isolated from fetal liver.

2018-06-08 | GSE112860 | GEO

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