Molecular mechanism of monoamine oxidase A gene regulation under inflammation and ischemia‐like conditions: key roles of the transcription factors GATA2, Sp1 and TBP. (16th April 2015)

• Record Type: Journal Article
• Authors: Gupta, Vinayak; Khan, Abrar A.; Sasi, Binu K.; Mahapatra, Nitish R.
• Is Part Of: Journal of neurochemistry. Volume 134:Number 1(2015:Jul.)
• Page Start: 21
• Page End: 38
• Publication Date: 2015-04-16
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13099
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc13099-abs-0001"> <title>Abstract</title> <p>Monoamine oxidase A (MAOA) plays important roles in the pathogenesis of several neurological and cardiovascular disorders. The mechanism of transcriptional regulation of <italic>MAOA</italic> under basal and pathological conditions, however, remains incompletely understood. Here, we report systematic identification and characterization of <italic>cis</italic> elements and transcription factors that govern the expression of <italic>MAOA</italic> gene. Extensive computational analysis of <italic>MAOA</italic> promoter, followed by 5′‐promoter deletion/reporter assays, revealed that the −71/−40 bp domain was sufficient for its basal transcription. Gel‐shift and chromatin immunoprecipitation assays provided evidence of interactions of the transcription factors GATA‐binding protein 2 (GATA2), Sp1 and TATA‐binding protein (TBP) with this proximal promoter region. Consistently, over‐expression of GATA2, Sp1 and TBP augmented <italic>MAOA</italic> promoter activity in a coordinated manner. In corroboration, siRNA‐mediated down‐regulation of GATA2/Sp1/TBP repressed the endogenous <italic>MAOA</italic> expression as well as transfected <italic>MAOA</italic> promoter activity. Tumor necrosis factor‐α and forskolin activated <italic>MAOA</italic> transcription that was reversed by Sp1 siRNA; in support, tumor necrosis factor‐α‐ and forskolin‐induced activities were enhanced by ectopic over‐expression of Sp1. On the other hand, <italic>MAOA</italic> transcription was diminished upon exposure of neuroblasts or cardiac myoblasts to ischemia‐like conditions because of reduced binding of GATA2/Sp1/TBP with <italic>MAOA</italic> promoter. In conclusion, this study revealed previously unknown roles of GATA2, Sp1 and TBP in modulating <italic>MAOA</italic> expression under basal as well as pathophysiological conditions such as inflammation and ischemia, thus providing new insights into the molecular basis of aberrant <italic>MAOA</italic> expression in neuronal/cardiovascular disease states. <graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgj10cncktc" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> Dysregulation of monoamine oxidase A (MAOA) have been implicated in several behavioral and neuronal disease states. Here, we identified three crucial transcription factors (GATA2, Sp1 and TBP) that regulate <italic>MAOA</italic> gene expression in a coordinated manner. Aberrant <italic>MAOA</italic> expression under pathophysiological conditions including inflammation and ischemia is mediated by altered binding of GATA2/Sp1/TBP with <italic>MAOA</italic> proximal promoter. Thus, these findings provide new insights into pathogenesis of several common diseases. GATA2, GATA‐binding protein 2; Sp1, specificity protein 1; TBP, TATA‐binding protein.</p> </abstract>