Epigenetic landscapes of intracranial aneurysm risk haplotypes implicate enhancer function of endothelial cells and fibroblasts in dysregulated gene expression

Poppenberg, Kerry E.; Zebraski, Haley R; Avasthi, Naval; Waqas, Muhammad; Siddiqui, Adnan H.; Jarvis, James N.; Tutino, Vincent M.

doi:10.1186/s12920-021-01007-9

Cited by 5 publications

(3 citation statements)

References 64 publications

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“…Furthermore, the IA wall may locally release chemokines and chemoattractant cytokines (such as IL-1, IL-8, and IL-17), which can peripherally activate circulating immune cells in the blood [15]. Alternatively, aberrant gene expression may be inherent, resulting from heritable genetic factors (something we have explored in separate studies [36,37]), or could even be promulgated by combinations of risk factors that are commonly associated with IA.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

Tutino

Ishii

et al. 2021

Diagnostics

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The rupture of an intracranial aneurysm (IA) causes devastating hemorrhagic strokes. Yet, most IAs remain asymptomatic and undetected until they rupture. In the search for circulating biomarkers of unruptured IAs, we previously performed transcriptome profiling on whole blood and identified an IA-associated panel of 18 genes. In this study, we seek to determine if these genes are also differentially expressed within the IA lumen, which could provide a mechanistic link between the disease and the observed circulating gene expression patterns. To this end, we collected blood from the lumen of 37 IAs and their proximal parent vessels in 31 patients. The expression levels of 18 genes in the lumen and proximal vessel were then measured by quantitative polymerase chain reaction. This analysis revealed that the expression of 6/18 genes (CBWD6, MT2A, MZT2B, PIM3, SLC37A3, and TNFRSF4) was significantly higher in intraluminal blood, while the expression of 3/18 genes (ST6GALNAC1, TCN2, and UFSP1) was significantly lower. There was a significant, positive correlation between intraluminal and proximal expression of CXCL10, MT2A, and MZT2B, suggesting local increases of these genes is reflected in the periphery. Expression of ST6GALNAC1 and TIFAB was significantly positively correlated with IA size, while expression of CCDC85B was significantly positively correlated with IA enhancement on post-contrast MRI, a metric of IA instability and risk. In conclusion, intraluminal expression differences in half of the IA-associated genes observed in this study provide evidence for IA tissue-mediated transcriptional changes in whole blood. Additionally, some genes may be informative in assessing IA risk, as their intraluminal expression was correlated to IA size and aneurysmal wall enhancement.

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Section: Discussionmentioning

confidence: 99%

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

Tutino

Ishii

et al. 2021

Diagnostics

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“…CDKN2C positively related genes (CPRGs) were selected from genes with positive expression correlation with CDKN2C expression in > 35% (5/13) of the datasets. The predicted transcription factors (TFs) for CDKN2C expression were screened from the Cistrome Data Browser [ 23 – 27 ] with a cutoff score of > 0.9 (calculated using chromatin immunoprecipitation sequencing data). Matched sequences between predicted TFs and CDKN2C were identified by JASPAR [ 28 ] and Find Individual Motif Occurences [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

Clinical significance of cyclin-dependent kinase inhibitor 2C expression in cancers: from small cell lung carcinoma to pan-cancers

Chen²,

Li³

et al. 2022

BMC Pulm Med

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Background Cyclin-dependent kinase inhibitor 2C (CDKN2C) was identified to participate in the occurrence and development of multiple cancers; however, its roles in small cell lung carcinoma (SCLC) remain unclear. Methods Differential expression analysis of CDKN2C between SCLC and non-SCLC were performed based on 937 samples from multiple centers. The prognosis effects of CDKN2C in patients with SCLC were detected using both Kaplan–Meier curves and log-rank tests. Using receiver-operating characteristic curves, whether CDKN2C expression made it feasible to distinguish SCLC was determined. The potential mechanisms of CDKN2C in SCLC were investigated by gene ontology terms and signaling pathways (Kyoto Encyclopedia of Genes and Genomes). Based on 10,080 samples, a pan-cancer analysis was also performed to determine the roles of CDKN2C in multiple cancers. Results For the first time, upregulated CDKN2C expression was detected in SCLC samples at both the mRNA and protein levels (p of Wilcoxon rank-sum test < 0.05; standardized mean difference = 2.86 [95% CI 2.20–3.52]). Transcription factor FOXA1 expression may positively regulate CDKN2C expression levels in SCLC. High CDKN2C expression levels were related to the poor prognosis of patients with SCLC (hazard ratio > 1, p < 0.05) and showed pronounced effects for distinguishing SCLC from non-SCLC (sensitivity, specificity, and area under the curve ≥ 0.95). CDKN2C expression may play a role in the development of SCLC by affecting the cell cycle. Furthermore, the first pan-cancer analysis revealed the differential expression of CDKN2C in 16 cancers (breast invasive carcinoma, etc.) and its independent prognostic significance in nine cancers (e.g., adrenocortical carcinoma). CDKN2C expression was related to the immune microenvironment, suggesting its potential usefulness as a prognostic marker in immunotherapy. Conclusions This study identified upregulated CDKN2C expression and its clinical significance in SCLC and other multiple cancers, suggesting its potential usefulness as a biomarker in treating and differentiating cancers.

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“…However, there is little information regarding its role in intracranial aneurysm. Recently, epigenetics has become a new research hotspot in intracranial aneurysm (Poppenberg et al 2021). Epigenetics, defined as transcriptional memory which alters gene expression without changing the genome can be distinguished into three kinds, histone modifications, and non-coding RNAs (Zurek et al 2021).…”

Section: Introductionmentioning

confidence: 99%

JMJD3 is Involved in Intracranial Aneurysm Development by Regulating DLX2 Expression through H3K27me3 Modification

Wang¹,

2023

Tohoku J. Exp. Med.

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Intracranial aneurysms are dilatations in the arteries that supply blood to the brain. Rupture of an IA leads to a subarachnoid hemorrhage, which is fatal in about 50% of the cases. Microarray-based mRNA expression studies provide unbiased information about molecular mechanisms of intracranial aneurysm and the foundation for functional studies. In this study, by using a GEO dataset, we identified distal-less homeobox 2 (DLX2) as a significantly upregulated gene in AI and set to dissect its functional role and upstream mechanism. Here, we found that DLX2 expression was elevated in intracranial aneurysm patients. Silencing of DLX2 suppressed the proliferative capacity of human aortic vascular smooth muscle cells (HA-VSMC) and promoted their apoptosis. Moreover, loss of DLX2 promoted collagen I and collagen III and inhibited the levels of MMP2/9 and pro-inflammatory factors. Additionally, jumonji domain-containing protein 3 demethylase (JMJD3) promoted DLX2 expression by inhibiting H3K27me3 modification. Depletion of JMJD3 exerted the same function as DLX2 in vitro and in vivo, whereas overexpression of DLX2 in the presence of JMJD led to accentuated intracranial aneurysm progression and enhanced HA-VSMC survival. We conclude that JMJD3 promotes DLX2 expression through inhibition of H3K27me3 modification, thereby promoting AI formation.

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Epigenetic landscapes of intracranial aneurysm risk haplotypes implicate enhancer function of endothelial cells and fibroblasts in dysregulated gene expression

Cited by 5 publications

References 64 publications

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

Clinical significance of cyclin-dependent kinase inhibitor 2C expression in cancers: from small cell lung carcinoma to pan-cancers

JMJD3 is Involved in Intracranial Aneurysm Development by Regulating DLX2 Expression through H3K27me3 Modification

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