Inhibition of endothelial histone deacetylase 2 shifts endothelial-mesenchymal transitions in cerebral arteriovenous malformation models
Yan Zhao, … , Kristina I. Boström, Yucheng Yao
Yan Zhao, … , Kristina I. Boström, Yucheng Yao
Published May 23, 2024
Citation Information: J Clin Invest. 2024;134(15):e176758. https://doi.org/10.1172/JCI176758.
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Research Article Vascular biology

Inhibition of endothelial histone deacetylase 2 shifts endothelial-mesenchymal transitions in cerebral arteriovenous malformation models

Abstract

Cerebral arteriovenous malformations (AVMs) are the most common vascular malformations worldwide and the leading cause of hemorrhagic strokes that may result in crippling neurological deficits. Here, using recently generated mouse models, we uncovered that cerebral endothelial cells (ECs) acquired mesenchymal markers and caused vascular malformations. Interestingly, we found that limiting endothelial histone deacetylase 2 (HDAC2) prevented cerebral ECs from undergoing mesenchymal differentiation and reduced cerebral AVMs. We found that endothelial expression of HDAC2 and enhancer of zeste homolog 1 (EZH1) was altered in cerebral AVMs. These alterations changed the abundance of H4K8ac and H3K27me in the genes regulating endothelial and mesenchymal differentiation, which caused the ECs to acquire mesenchymal characteristics and form AVMs. This investigation demonstrated that the induction of HDAC2 altered specific histone modifications, which resulted in mesenchymal characteristics in the ECs and cerebral AVMs. The results provide insight into the epigenetic impact on AVMs.

Authors

Yan Zhao, Xiuju Wu, Yang Yang, Li Zhang, Xinjiang Cai, Sydney Chen, Abigail Vera, Jaden Ji, Kristina I. Boström, Yucheng Yao

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Figure 7

Alterations in H4K8ac and H3K27me3 in gene regulations of endothelial and mesenchymal differentiation.

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Alterations in H4K8ac and H3K27me3 in gene regulations of endothelial an...
(A and B) Histone acetylation (A) and methylation (B) in CD31+CD45– cerebral ECs isolated from VE-cadherincre/ERT2Mgpfl/fl mice treated with tamoxifen. Mgpfl/fl mice were used as control (n = 4). (C) ChIP-Seq of H4K8ac and H3K27me3 in CD31+CD45– cerebral ECs isolated from VE-cadherincre/ERT2Mgpfl/fl and Mgpfl/fl mice treated with tamoxifen. (D) Heatmap of the occupancy of H4K8ac around the regulatory regions of endothelial markers and of H3K27me3 around the regulatory regions of mesenchymal and stem cell markers. Each ChIP library was constructed using cells isolated and pooled from 3 mice. Peaks were identified with more than 4-fold enrichment and an FDR of 0.1% compared with controls; log2-transformed peak densities were then used to generate occupancy heatmaps. (E) Plots of the occupancy of H4K8ac at the Ezh1 gene locus from ChIP-Seq data. (F) Plots of the occupancy of H3K27me3 at the Jagged1 and Jagged2 gene loci from ChIP-Seq data. (G) Time course of ChIP assays of H4K8ac and H3K27me3 in the promoters of Kdr and Snai1 in CD31+CD45– cerebral ECs isolated from VE-cadherincre/ERT2Mgpfl/fl and Mgpfl/fl mice treated with tamoxifen (n = 6). Data represented in A and B were analyzed for statistical significance using unpaired, 2-tailed Student’s t test. Data represented in G were analyzed for statistical significance using ANOVA with post hoc Tukey’s test. The bounds of the boxes show upper and lower quartiles with data points. The lines in the boxes show the medians. Error bars represent maximal and minimal values. ***P < 0.0001.