PRDM16 controls smooth muscle cell fate in atherosclerosis [RNA-Seq]
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ABSTRACT:
PROVIDER: PRJNA1304974 | ENA |
REPOSITORIES: ENA
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Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.
2025-08-28 | GSE305272 | GEO
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.
2025-08-28 | GSE305275 | GEO
Project description:PRDM16 controls smooth muscle cell fate in atherosclerosis [ChIP-Seq]
| PRJNA1304970 | ENA
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.
2025-08-28 | GSE305277 | GEO
Project description:PRDM16 controls smooth muscle cell fate in atherosclerosis: Fixed-cell scRNAseq datasets [scRNA-seq]
| PRJNA1304978 | ENA
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce various cell phenotypes in response to pathologic stimuli1-3. In atherosclerosis, these phenotypically modulated SMCs regulate plaque composition and influence the risk of major adverse cardiovascular events4,5. We found that PRDM16, a transcription factor that is genetically associated with cardiovascular disease, is highly expressed in arterial SMCs and downregulated during SMC fate switching in human and mouse atherosclerosis. Loss of Prdm16 in SMCs of mice activates a synthetic modulation program under homeostatic conditions. Single cell analyses show that loss of Prdm16 drives a synthetic program in all SMC populations. Upon exposure to atherogenic stimuli, SMC-selective Prdm16 deficient mice develop SMC-rich, fibroproliferative plaques that contain few foam cells. Acute loss of Prdm16 results in the formation of collagen-rich lesions with thick fibrous caps. Reciprocally, increasing PRDM16 expression in SMCs blocks synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, these results define PRDM16 as a critical determinant of SMC identity and atherosclerotic lesion composition.
| S-EPMC11870537 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain–containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell–specific (VSMC-specific) Prdm16-knockout (Prdm16SMKO) mice already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes, including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase that can degrade various ECMs. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment.
2023-06-08 | GSE222440 | GEO
Project description:This SuperSeries is composed of the following subset Series:; GSE13835: Smooth muscle cells in atherosclerosis-prone and resistant regions of the aorta of C57Bl/6 mice at age of 4 months; GSE13836: Smooth muscle cells in atherosclerosis-prone and resistant regions of the aorta of apoE-/- mice at age of 4 months Experiment Overall Design: Refer to individual Series
2009-05-27 | E-GEOD-13865 | biostudies-arrayexpress
Project description:Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC transdifferentiation into macrophage-like SMCs. Furthermore, during transdifferentiation, the SMCs' expression of PADI4 upregulating and SMC generated extracellular trap, a web-like structure, which plays key role in the development of atherosclerosis plaque. To reveal the function of SMC's generating ETs during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of mouse atherosclerotic plaques.
2022-11-04 | GSE197073 | GEO
Project description:Brown adipose tissue (BAT) dissipates chemical energy in the form of heat, as a defense against hypothermia and obesity. Current evidence indicates that brown adipocytes arise from Myf5+-dermotomal precursors through the action of a PRDM16-C/EBP-_ transcriptional complex; however, the underlying mechanisms that determine lineage specification and maintenance of brown adipose cells remain poorly understood. Here we study the role of euchromatic histone-lysine N-methyltransferase 1 (EHMT1), a brown fat-enriched lysine methyltransferase, as an essential enzymatic component of the PRDM16 transcriptional complex and controls brown adipose cell fate. To identify targets and function of EHMT1, we performed genome-wide gene expression profiling of BAT from control mouce (Ehmt1flox/flox), Ehmt1Myf5 KO mouse (Myf5-Cre+/-; Ehmt1flox/flox) and Ehmt1adipo KO mouse (Adipo-Cre+/-; Ehmt1flox/flox). Loss of EHMT1 in Myf5+ lineage causes a near total loss of brown fat characteristics and induces muscle-selective gene program in vivo. In addition, adipose-specific deletion of EHMT1 by Adipo-Cre leads to a marked reduction of the thermogenic and fat oxidation genes.
2013-11-07 | E-MTAB-1704 | biostudies-arrayexpress