The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1074411 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27907700_1.fastq.gz | Fastqsanger.gz | |||
| SRR27907700_2.fastq.gz | Fastqsanger.gz | |||
| SRR27907701_1.fastq.gz | Fastqsanger.gz | |||
| SRR27907701_2.fastq.gz | Fastqsanger.gz | |||
| SRR27907702_1.fastq.gz | Fastqsanger.gz |
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Project description:Cardiac injury following myocardial infarction exhibits a circadian pattern, yet the underlying mechanism remains unclear. To elucidate genes governing circadian variation of myocardial injury, we conducted transcriptomic profiling of left-ventricular tissues from mice or humans experiencing myocardial injury at different daytimes. Through comprehensive analyses, including transgenic mouse models and functional studies, we identified BMAL1 as a pivotal transcription factor modulating diurnal variation of myocardial injury. Remarkably, we discovered that BMAL1 regulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with HIF2A. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2F/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1. Furthermore, we confirmed amphiregulin (AREG) as a transcriptional target of the BMAL1/HIF2A heterodimer, critical for modulating circadian variation of myocardial injury. Finally, targeting the BMAL1/HIF2A-AREG pathway via timed AREG administration or enhancing circadian rhythm pharmacologically offered significant cardioprotection, implicating this pathway in treating ischemic heart disease.
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Project description:Analysis of heart of Hypoxia-inducible 2 alpha-deficient mice, specific in cardiomyocytes (Hif2aloxP/loxP Myosin Cre+) subjected to myocardial ishcemia reperfusion. Hif2a belongs to the family of transcription factors, that regulate a transcriptional response to tissue hypoxia.
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Project description:HIF2a function is both necessary and sufficient for the growth of VHL-null clear cell Renal Cell Carcinoma (ccRCC). Targeting HIF2a function can therefore be a promising therapeutic strategy. We used microarray analysis to characterize a novel pharmacological inhibitor of HIF2a named PT2399. By comparing genes that are responsive to PT2399 in parental cells vs cells lacking HIF2a, by virtue of CRISPR-mediated genetic editing, we characterized gene signatures that are regulated by PT2399 in a HIF2a dependent manner. Cells were treated with either DMSO (control) or 2uM PT2399 for indicated time periods, total RNA was extracted and analyzed. Please note that the experiments with 786O Parental and HIF2a null cells were conducted independently.
2016-07-03 | E-GEOD-72959 | biostudies-arrayexpress
Project description:Circadian clocks are cell autonomous, transcriptionally-based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are two transcription factors, CLOCK and BMAL1. Previous studies in our laboratory have highlighted roles for CLOCK in cardiac physiology/pathophysiology. Here, we describe transcriptional, metabolic, and functional consequences of cardiomyocyte-specific Bmal1 knockout (CBK). Microarray analysis revealed 2037 differentially expressed genes in CBK hearts, many of which were previously identified in cardiomyocyte-specific Clock mutant (CCM) hearts. Subsequent analysis showed that Beta-hydroxybutyrate dehydrogenase 1 mRNA, protein, and enzymatic activity are markedly depressed in both CBK and CCM hearts, as is myocardial Beta-hydroxybutyrate oxidation, revealing a novel role for the circadian clock in ketone body utilization. A number of genes encoding for collagen isoforms were identified as oscillating in a time-of-day-dependent manner in wild-type, but not CBK, hearts, including col3a1, col4a1, and col4a2. Chronic induction of collagen isoform genes in CBK hearts was associated with severe age-dependent depression of cardiac function. Development of cardiomyopathy in CBK mice was associated with early mortality; all CBK mice die by one year of age. These studies highlight novel critical functions for BMAL1 in the heart, including regulation of ketone body metabolism and the extracellular matrix. RNA from whole hearts collected every 3 hours for 24 hours from wildtype and CBK mice was isolated and analyzed using MouseRef-8_V2 BeadChips (Illumina, Inc.). The 24-hour data were examined for rhythmicity using cosinor analysis and differences in rhythmicity between genotype groups were further examined for differences in the model fitting parameters.
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2017-12-01 | E-MTAB-5329 | biostudies-arrayexpress
Project description:Circadian clocks are cell autonomous, transcriptionally-based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are two transcription factors, CLOCK and BMAL1. Previous studies in our laboratory have highlighted roles for CLOCK in cardiac physiology/pathophysiology. Here, we describe transcriptional, metabolic, and functional consequences of cardiomyocyte-specific Bmal1 knockout (CBK). Microarray analysis revealed 2037 differentially expressed genes in CBK hearts, many of which were previously identified in cardiomyocyte-specific Clock mutant (CCM) hearts. Subsequent analysis showed that Beta-hydroxybutyrate dehydrogenase 1 mRNA, protein, and enzymatic activity are markedly depressed in both CBK and CCM hearts, as is myocardial Beta-hydroxybutyrate oxidation, revealing a novel role for the circadian clock in ketone body utilization. A number of genes encoding for collagen isoforms were identified as oscillating in a time-of-day-dependent manner in wild-type, but not CBK, hearts, including col3a1, col4a1, and col4a2. Chronic induction of collagen isoform genes in CBK hearts was associated with severe age-dependent depression of cardiac function. Development of cardiomyopathy in CBK mice was associated with early mortality; all CBK mice die by one year of age. These studies highlight novel critical functions for BMAL1 in the heart, including regulation of ketone body metabolism and the extracellular matrix.
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2016-01-01 | GSE72959 | GEO
Project description:VHL loss is the most common genetic alteration event in ccRCC. VHL loss stabilizes hypoxia-inducible factor-2 alpha (HIF2a). We compared the changes in transcriptomics profiles after VHL restoration or HIF2a siRNA knockdown in 786-O cells.
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Project description:TMT analysis of proteomic changes in the gastrocnemius skeletal muscles of WT and Bmal1-KO mice, and Bmal1-KO mice rescued with AAV-mediated muscle-specific expression of Bmal1.
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Project description:The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of thousands of genes and enable biological functions to anticipate the daily environmental variations. Consistent with the wide range of biological functions under clock control, rhythmic gene expression is tissue-specific, and this even if the clockwork mechanism is identical in every cell. Here we show that BMAL1 DNA binding is largely tissue-specific, through mechanisms involving differences in chromatin accessibility between tissues as well as co-binding of tissue-specific transcription factors. Our results also indicate that the ability of BMAL1 to drive tissue-specific rhythmic transcription not only relies on the activity of BMAL1 cis-regulatory elements (CREs), but also on the activity of neighboring CREs. Characterization of the physical interactions between BMAL1 CREs and other CREs by RNA Polymerase II ChIA-PET in the mouse liver reveals that most interactions are stable over the course of the day, and suggests that BMAL1-mediated rhythmic transcription relies on its ability to regulate the transcriptional activity of other CREs. Our data therefore suggest that much of BMAL1 target gene transcription depends on BMAL1 capacity at rhythmically regulating a network of enhancers.
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