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

Published on 2019-11-08T13:10:28Z (GMT) by
<div><p>The histone deacetylases (HDACs)-dependent mechanisms regulating gene transcription of the Na<sup>+</sup>/Ca<sup>+</sup> exchanger isoform 3 (<i>ncx3</i>) 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 <i>ncx3</i> promoter. Importantly, DREAM, HDAC4, and HDAC5 recruitment to the <i>ncx3</i> gene was increased in the temporoparietal cortex of rats subjected to transient middle cerebral artery occlusion (tMCAO), with a consequent histone-deacetylation of <i>ncx3</i> 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 <i>ncx3</i> knockdown. Collectively, we found that: (1) DREAM/HDAC4/HDAC5 complex epigenetically down-regulates <i>ncx3</i> gene transcription after stroke, and (2) pharmacological inhibition of class IIa HDACs reduces stroke-induced neurodetrimental effects.</p></div>

Cite this collection

Formisano, Luigi; Laudati, Giusy; Guida, Natascia; Mascolo, Luigi; Serani, Angelo; Cuomo, Ornella; et al. (2019): HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage. SAGE Journals. Collection. https://doi.org/10.25384/SAGE.c.4730267.v1