Histone methyltransferase DOT1L regulates macrophage inflammatory responses and atherosclerotic plaque stability by affecting SREBPs and lipid biosynthesis [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA794854 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17454754.fastq.gz | Fastqsanger.gz | |||
| SRR17454758.fastq.gz | Fastqsanger.gz | |||
| SRR17454759.fastq.gz | Fastqsanger.gz | |||
| SRR17454760.fastq.gz | Fastqsanger.gz | |||
| SRR17454765.fastq.gz | Fastqsanger.gz |
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Project description:Macrophages are critical immune cells in inflammatory diseases and their differentiation and function are tightly regulated by epigenetic alterations. H3K79 methylation is an epigenetic modification associated with active gene expression and DOT1L is the only histone methyltransferase for H3K79. Here we determine the role of DOT1L in macrophages by applying a selective DOT1L inhibitor in mouse and human macrophages and using myeloid-specific Dot1l deficient mice. We found that DOT1L directly regulates macrophage function by controlling lipid biosynthesis gene programs including central lipid regulators like sterol regulatory element-binding proteins SREBP1 and SREBP2. DOT1L inhibition also leads to macrophage hyperactivation which is associated with disrupted SREBP pathways. In vivo, myeloid Dot1l deficiency reduces atherosclerotic plaque stability and increases the activation of inflammatory plaque macrophages. Our data show that DOT1L is a crucial regulator of macrophage inflammatory responses and lipid regulatory pathways and suggests a high relevance of H3K79 methylation in inflammatory disease.
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Project description:Macrophages are critical immune cells in inflammatory diseases and their differentiation and function are tightly regulated by epigenetic alterations. H3K79 methylation is an epigenetic modification associated with active gene expression and DOT1L is the only histone methyltransferase for H3K79. Here we determine the role of DOT1L in macrophages by applying a selective DOT1L inhibitor in mouse and human macrophages and using myeloid-specific Dot1l deficient mice. We found that DOT1L directly regulates macrophage function by controlling lipid biosynthesis gene programs including central lipid regulators like sterol regulatory element-binding proteins SREBP1 and SREBP2. DOT1L inhibition also leads to macrophage hyperactivation which is associated with disrupted SREBP pathways. In vivo, myeloid Dot1l deficiency reduces atherosclerotic plaque stability and increases the activation of inflammatory plaque macrophages. Our data show that DOT1L is a crucial regulator of macrophage inflammatory responses and lipid regulatory pathways and suggests a high relevance of H3K79 methylation in inflammatory disease.
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Project description:Macrophages are critical immune cells in inflammatory diseases and their differentiation and function are tightly regulated by epigenetic alterations. H3K79 methylation is an epigenetic modification associated with active gene expression and DOT1L is the only histone methyltransferase for H3K79. Here we determine the role of DOT1L in macrophages by applying a selective DOT1L inhibitor in mouse and human macrophages and using myeloid-specific Dot1l deficient mice. We found that DOT1L directly regulates macrophage function by controlling lipid biosynthesis gene programs including central lipid regulators like sterol regulatory element-binding proteins SREBP1 and SREBP2. DOT1L inhibition also leads to macrophage hyperactivation which is associated with disrupted SREBP pathways. In vivo, myeloid Dot1l deficiency reduces atherosclerotic plaque stability and increases the activation of inflammatory plaque macrophages. Our data show that DOT1L is a crucial regulator of macrophage inflammatory responses and lipid regulatory pathways and suggests a high relevance of H3K79 methylation in inflammatory disease.
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Project description:Macrophages are critical immune cells in inflammatory diseases and their differentiation and function are tightly regulated by epigenetic alterations. H3K79 methylation is an epigenetic modification associated with active gene expression and DOT1L is the only histone methyltransferase for H3K79. Here we determine the role of DOT1L in macrophages by applying a selective DOT1L inhibitor in mouse and human macrophages and using myeloid-specific Dot1l deficient mice. We found that DOT1L directly regulates macrophage function by controlling lipid biosynthesis gene programs including central lipid regulators like sterol regulatory element-binding proteins SREBP1 and SREBP2. DOT1L inhibition also leads to macrophage hyperactivation which is associated with disrupted SREBP pathways. In vivo, myeloid Dot1l deficiency reduces atherosclerotic plaque stability and increases the activation of inflammatory plaque macrophages. Our data show that DOT1L is a crucial regulator of macrophage inflammatory responses and lipid regulatory pathways and suggests a high relevance of H3K79 methylation in inflammatory disease.
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Project description:In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content. A smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies.
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