Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms

Davis, Frank M.; Tsoi, Lam C.; Melvin, William J.; denDekker, Aaron D.; Wasikowski, Rachael; Joshi, Amrita; Wolf, Sonya; Obi, Andrea; Billi, Allison C.; Xing, Xianying; Audu, Christopher O.; Moore, Bethany B.; Kunkel, Steven L.; Daugherty, Alan; Lü, Hong; Guðjónsson, Jóhann E.; Gallagher, Katherine A.

doi:10.1084/jem.20201839

Cited by 78 publications

(90 citation statements)

References 98 publications

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“…In addition to IL-6 related pathways, we found that IL1B was linked more often to nonbaseline open REs in AAA patients compared with healthy controls in AoSMC (adjusted P = 2e-4). IL1B has previously been found to be up-regulated in AAA patients by RNA-seq (adjusted P = 2e-3) ( 13 ) and quantitative PCR ( P < 0.05) ( 26 ). These findings contribute to understanding the regulatory mechanisms of IL1B in AAA pathogenesis.…”

Section: Resultsmentioning

confidence: 98%

“…In the IL-6-mediated signaling pathway, five genes ( IL6ST , SOCS3 , MIR99A , MIRLET7C , and MIR125B2 ) were the targets of nonbaseline open REs (i.e., RE with nonbaseline openness). SOCS3 was detected to be significantly up-regulated in AAA patients in bulk RNA-sequencing (RNA-seq) data ( 13 ) and also up-regulated in the smooth muscle cell cluster from single-cell RNA-seq in AAA patients compared with control samples ( 26 ). In the negative regulation of IL-6-mediated signaling pathway, three microRNAs (miRNAs) ( MIRLET7C , MIR99A , and MIR125B2 ) were the targets of nonbaseline open REs.…”

Section: Resultsmentioning

confidence: 99%

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Leveraging cell-type-specific regulatory networks to interpret genetic variants in abdominal aortic aneurysm

Chen

Zhu

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Abdominal aortic aneurysm (AAA) is a common degenerative cardiovascular disease whose pathobiology is not clearly understood. The cellular heterogeneity and cell-type-specific gene regulation of vascular cells in human AAA have not been well-characterized. Here, we performed analysis of whole-genome sequencing data in AAA patients versus controls with the aim of detecting disease-associated variants that may affect gene regulation in human aortic smooth muscle cells (AoSMC) and human aortic endothelial cells (HAEC), two cell types of high relevance to AAA disease. To support this analysis, we generated H3K27ac HiChIP data for these cell types and inferred cell-type-specific gene regulatory networks. We observed that AAA-associated variants were most enriched in regulatory regions in AoSMC, compared with HAEC and CD4+ cells. The cell-type-specific regulation defined by this HiChIP data supported the importance of ERG and the KLF family of transcription factors in AAA disease. The analysis of regulatory elements that contain noncoding variants and also are differentially open between AAA patients and controls revealed the significance of the interleukin-6-mediated signaling pathway. This finding was further validated by including information from the deleteriousness effect of nonsynonymous single-nucleotide variants in AAA patients and additional control data from the Medical Genome Reference Bank dataset. These results shed important insights into AAA pathogenesis and provide a model for cell-type-specific analysis of disease-associated variants.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Leveraging cell-type-specific regulatory networks to interpret genetic variants in abdominal aortic aneurysm

Chen

Zhu

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…JMJD3 depletion in foam cells suppresses pro-fibrotic pathways, an important hallmark for atherosclerosis ( 38 ). Myeloid JMJD3 deficiency also leads to advanced atherosclerosis ( 88 ). Histone modification alterations, such as reduction of H3K9 and H3K27 methylation levels, have also been observed in patients with atherosclerotic plaques and carotid artery stenosis ( 20 ).…”

Section: Histone Methylation In Cvd Progressionmentioning

confidence: 99%

Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases

Yang

Luan

Yuan

et al. 2021

Front. Cardiovasc. Med.

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The epidemic of cardiovascular diseases (CVDs) is predicted to spread rapidly in advanced countries accompanied by the high prevalence of risk factors. In terms of pathogenesis, the pathophysiology of CVDs is featured by multiple disorders, including vascular inflammation accompanied by simultaneously perturbed pathways, such as cell death and acute/chronic inflammatory reactions. Epigenetic alteration is involved in the regulation of genome stabilization and cellular homeostasis. The association between CVD progression and histone modifications is widely known. Among the histone modifications, histone methylation is a reversible process involved in the development and homeostasis of the cardiovascular system. Abnormal methylation can promote CVD progression. This review discusses histone methylation and the enzymes involved in the cardiovascular system and determine the effects of histone methyltransferases and demethylases on the pathogenesis of CVDs. We will further demonstrate key proteins mediated by histone methylation in blood vessels and review histone methylation-mediated cardiomyocytes and cellular functions and pathways in CVDs. Finally, we will summarize the role of inhibitors of histone methylation and demethylation in CVDs and analyze their therapeutic potential, based on previous studies.

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Innate immune cells are crucial in the development and regulation of cardiovascular disease. In this issue, two groups, Davis et al (2021.

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mentioning

confidence: 99%

“…The highly interesting mechanistic study by Davis et al (2021) investigated the role of macrophages within abdominal aortic aneurysm development. Pro-inflammatory macrophages differentiate and proliferate from hematopoietic progenitor cells and show an important influence on aortic expansion.…”

mentioning

confidence: 99%