DNA methylation signatures on vascular differentiation genes are aberrant in vessels of human cerebral arteriovenous malformation nidus

Abstract

Arteriovenous malformation (AVM) is a tangle of arteries and veins, rupture of which can result in catastrophic hemorrhage in vulnerable sites such as the brain. Cerebral AVM is associated with a high mortality rate in humans. The causative factor or the stimulus at the artery-venous junction and the molecular basis of the development and progression of cerebral AVM remain unknown. While it is known that aberrant hemodynamic forces in the artery-vein junction contribute to the development of AVMs, the mechanistic pathways are unclear. Given that various environmental stimuli modulate epigenetic modifications on the chromatin of cells, we speculated that misregulated DNA methylome could lead to cerebral AVM development. To identify the aberrant epigenetic signatures, we used AVM nidus tissues and analyzed the global DNA methylome using the Infinium DNA methylome array. We observed significant alterations of DNA methylation in the genes associated with the vascular developmental pathway. Further, we validated the DNA hypermethylation by DNA bisulfite sequencing analysis of selected genes from human cerebral AVM nidus. Taken together, we provide the first experimental evidence for aberrant epigenetic signatures on the genes of vascular development pathway, in human cerebral AVM nidus.

Nicotinic Acid-Mediated Modulation of Metastasis-Associated Protein 1 Methylation and Inflammation in Brain Arteriovenous Malformation

“…This insight may help to predict the occurrence of stroke and serve as a target for treatment evaluation [30]. A previous study [10] showed that abnormal DNA methylation of vascular differentiation genes may be an important factor in BAVM lesions. It has also been observed that the hypermethylation of cyclin-dependent kinase inhibitor 2A (CDKN2A) can increase the risk of BAVM and has potential value for early diagnosis [31].…”

“…Researchers demonstrated that changes in local hemodynamics within a BAVM vascular mass might influence cellular metabolism, triggering epigenetic factors in endothelial cells [9]. Thomas et al [10] observed abnormal DNA methylation signatures in promoters of genes related to vascular development in their study of brain BAVMs tissue. Further, they believed that the presence of multiple alterations in DNA methylation and histone modification in genes linked to vascular development implicated these genes in BAVM development.…”