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.
Authors	Luigi Formisano, Giusy Laudati, Natascia Guida, Luigi Mascolo, Angelo Serani, Ornella Cuomo, Maria Cantile, Francesca Boscia, Pasquale Molinaro, Serenella Anzilotti, Vincenzo Pizzorusso, Gianfranco Di Renzo, Giuseppe Pignataro, Lucio Annunziato
Journal	Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 40 Issue 10 Pg. 2081-2097 (10 2020) ISSN: 1559-7016 [Electronic] United States
PMID	31696766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Histone Deacetylase Inhibitors Kcnip3 protein, rat Kv Channel-Interacting Proteins Neuroprotective Agents RNA, Small Interfering Repressor Proteins Slc8a3 protein, rat Sodium-Calcium Exchanger HDAC4 protein, rat Hdac5 protein, rat Histone Deacetylases
Topics	Animals Cerebral Cortex (pathology) Epigenesis, Genetic (physiology) Gene Expression Regulation (drug effects) Gene Knockdown Techniques Histone Deacetylase Inhibitors (pharmacology) Histone Deacetylases (genetics, metabolism) Humans Hypoxia, Brain (prevention & control) Infarction, Middle Cerebral Artery (pathology) Kv Channel-Interacting Proteins (antagonists & inhibitors, genetics, metabolism) Male Neurons (pathology) Neuroprotective Agents RNA, Small Interfering (pharmacology) Rats Rats, Sprague-Dawley Repressor Proteins (antagonists & inhibitors, genetics, metabolism) Sodium-Calcium Exchanger (genetics, metabolism) Stroke (drug therapy, genetics, pathology)

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