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Series GSE193873 Query DataSets for GSE193873
Status Public on Dec 01, 2023
Title Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in mice
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design Mice with cardiomyocytes-specific deletion of Prdm16 (cPrdm16 KO) at embryonic date 17 (E17) were used. Whole heart tissue was used to perform RNA sequencing.
 
Contributor(s) Boudina S, Landstrom AP
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Submission date Jan 18, 2022
Last update date Dec 01, 2023
Contact name Sihem Boudina
E-mail(s) sboudina@u2m2.utah.edu
Phone 8018644299
Organization name University of Utah
Department Nutrition and Integrative Physiology
Lab Boudina
Street address 15 N 2030 E bldg. 533 RM 3410b
City salt lake city
State/province Utah
ZIP/Postal code 84112
Country USA
 
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (5)
GSM5822841 15702X1 WT1
GSM5822842 15702X2 WT2
GSM5822843 15702X3 WT3
This SubSeries is part of SuperSeries:
GSE193878 Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans and mice
Relations
BioProject PRJNA798263

Download family Format
SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE193873_15702R_raw_counts.txt.gz 346.9 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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