Altering 5-hydroxymethylcytosine modification impacts ischemic brain injury

Abstract

Epigenetic modifications such as cytosine methylation and histone modification are linked to the pathology of ischemic brain injury. Recent research has implicated 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC) via oxidation by ten-eleven translocation (Tet) enzymes, in DNA methylation-related plasticity. Here we show that 5hmC abundance was increased after ischemic injury, and Tet2 was responsible for this increase; furthermore, inhibiting Tet2 expression abolished the increase of 5hmC caused by ischemic injury. The decrease in 5hmC modifications from inhibiting Tet2 activity was accompanied by increased infarct volume after ischemic injury. Genome-wide profiling of 5hmC revealed differentially hydroxymethylated regions (DhMRs) associated with ischemic injury, and DhMRs were enriched among the genes involved in cell junction, neuronal morphogenesis and neurodevelopment. In particular, we found that 5hmC modifications at the promoter region of brain-derived neurotrophic factor (BDNF) increased, which was accompanied by increased BDNF mRNA, whereas the inhibition of Tet2 reduced BDNF mRNA and protein expression. Finally, we show that the abundance of 5hmC in blood samples from patients with acute ischemic stroke was also significantly increased. Together, these data suggest that 5hmC modification could serve as both a potential biomarker and a therapeutic target for the treatment of ischemic stroke.

Tet1-dependent epigenetic modification of BDNF expression in dorsal horn neurons mediates neuropathic pain in rats

“…In addition, our current study found that nerve injury provoked the Tet1-dependent conversion of 5 mC to 5 hmC in the promoter region of bdnf , and then enhanced spinal bdnf transcription to underlie neuropathic pain development, all of which was reversed by focal knockdown of spinal Tet1 expression. Similarly, Tet2 was also demonstrated to promote 5 hmC enrichment at the bdnf promoter and increase the abundance of BDNF mRNA after ischemic injury; conversely, inhibition of Tet2 reduces the amounts of BDNF mRNA and protein26, implying the possible involvement of Tet family members other than Tet1. Particularly, the role of Tet2 in neuropathic pain warrants further study.…”

The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system

“…This resulted in demethylation of LINE‐1 and several specific genes involved in ROS detoxification and cell cycle arrest (Coulter et al , ). Similarly, in a mouse model of cerebral ischaemia, global 5hmC abundance and TET2 levels were increased in the ischaemic regions, and these responses were diminished in TET2 knockout mice (Miao et al , ). Induction of TET1 and TET3 proteins concomitant with either global or local increases in 5hmC marks has also been observed under hypoxia in different tumour cell lines, involving the transcription factors HIF1 or HIF2 (Mariani et al , ; Tsai et al , ; Wu et al , ) (Figure ).…”

Genomic distribution of 5-Hydroxymethylcytosine in mouse kidney and its relationship with gene expression

“…24 Miao et al reported that Tet2-mediated DNA hyroxymethylation is activated during brain ischemia injury and plays a protective role against stroke. 25 However, neither Tet1 nor Tet2 knockout has any significant influence on mouse embryonic or postnatal development (including the anatomic structures and physiological functions of kidney). 26,27 Considering the controversial results of Tet family genes in tissue homeostasis and oxidative stress, we are currently using Tet gene knockout mice to explore the functional role of Tet family genes in stress response including renal IR injury.…”