HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage

Abstract

The histone deacetylases (HDACs)-dependent mechanisms regulating gene transcription of the Na+/Ca+ exchanger isoform 3 ( ncx3) after stroke are still unknown. Overexpression or knocking-down of HDAC4/HDAC5 down-regulates or increases, respectively, NCX3 mRNA and protein. Likewise, MC1568 (class IIa HDACs inhibitor), but not MS-275 (class I HDACs inhibitor) increased NCX3 promoter activity, gene and protein expression. Furthermore, HDAC4 and HDAC5 physically interacted with the transcription factor downstream regulatory element antagonist modulator (DREAM). As MC1568, DREAM knocking-down prevented HDAC4 and HDAC5 recruitment to the ncx3 promoter. Importantly, DREAM, HDAC4, and HDAC5 recruitment to the ncx3 gene was increased in the temporoparietal cortex of rats subjected to transient middle cerebral artery occlusion (tMCAO), with a consequent histone-deacetylation of ncx3 promoter. Conversely, the tMCAO-induced NCX3 reduction was prevented by intracerebroventricular injection of siDREAM, siHDAC4, and siHDAC5. Notably, MC1568 prevented oxygen glucose deprivation plus reoxygenation and tMCAO-induced neuronal damage, whereas its neuroprotective effect was abolished by ncx3 knockdown. Collectively, we found that: (1) DREAM/HDAC4/HDAC5 complex epigenetically down-regulates ncx3 gene transcription after stroke, and (2) pharmacological inhibition of class IIa HDACs reduces stroke-induced neurodetrimental effects.

Epigenetic mechanisms and potential therapeutic targets in stroke

“…61,82 After transient MCAO in rats, overexpression or knockdown of HDAC4 and HDAC5, was shown to decrease or increase the expression of the neuroprotective Na þ /Ca 2þ exchanger 3 (NCX3), respectively. 83 RNA silencing of HDAC9 reduced endothelial injury and improved BBB integrity, thereby reduced inflammation, edema, and infarct following transient MCAO in rats. 84 HDAC9 expression was increased in the carotid plaques of stroke patients 85 and a single nucleotide polymorphism (SNP) in the HDAC9 gene has been associated with large artery atherosclerotic stroke in multiple stroke patient studies.…”

The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses

“…HDAC4 and HDAC5 physically interact with the transcription factor downstream regulatory element antagonist modulator (DREAM). A recent study showed that the DREAM/HDAC4/HDAC5 complex epigenetically down-regulates ncx3 gene transcription after stroke, and the pharmacological inhibition of class IIa HDACs reduces stroke-induced neurodetrimental effects [ 40 ].…”

“…HDAC inhibitors (iHDACs), which were effective in protecting the brain from ischemic damage, belonged to two chemical groups: (a) small carboxylates: valproic acid (VPA), sodium butyrate (SB), and sodium 4-phenylbutyrate (4-PBA); (b) Hydroxamate-containing compounds: suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) and others [ 55 ]. In cellular and animal models of ischemia, iHDACs have been shown to protect the brain from excitotoxicity, oxidative stress, endoplasmic reticulum stress, apoptosis, inflammation, and BBB damage [ 40 , 56 , 57 ]. They also promote angiogenesis, neurogenesis, and stem cell migration to damaged areas, which leads to functional recovery after brain ischemia [ 58 , 59 ].…”

Epigenetic Mechanisms Underlying Adult Post Stroke Neurogenesis

“…Ischemia alters the expression of multiple HDAC proteins, and these have become popular targets for preclinical neuroprotection studies in stroke [ 63 ]. Recent studies have demonstrated protective effects of HDAC inhibition by anti-inflammation and inhibition of proapoptotic factors in acute treatment of focal cerebral ischemia model of rats (1–6 h after stroke) with various compounds including valproic acid, trichostatin A and sodium butyrate [ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ].…”