MAS promoter regulation: a role for Sry and tyrosine nitration of the KRAB domain of ZNF274 as a feedback mechanism

Abstract

The ACE2/Ang-(1-7)/MAS axis of the renin-angiotensin system has emerged as a pathway of interest in treating both cardiovascular disorders and cancer. The MAS protein is known to bind to and be activated by Ang-(1-7); however mechanisms of this activation are just starting to be understood. Whereas there are strong biochemical data regarding regulation and activation of the AT1 and AT2 receptors, with models of how Ang II binds each receptor, fewer studies have characterized MAS. We characterize the MAS promoter and provide a potential feedback mechanism that would compensate for the MAS degradation following activation by Ang-(1-7). Analysis of ENCODE data for the MAS promoter revealed potential epigenetic control by KRAB/KAP1. A proximal promoter construct for the MAS gene was repressed by the SOX proteins SRY, SOX2, SOX3, and SOX14, of which SRY is known to interact with the KRAB domain. The proteins KRAB/KAP1 can both be tyrosine nitrated, causing the dissociation of the KAP-1 protein, and thus a potential loss of epigenetic control. Activation of MAS can lead to an increase in nitric oxide, suggesting feedback mechanisms of MAS on its own promoter. These results present a more complete view of MAS regulation and for the first time suggest biochemical outcomes for nitration to the KRAB domain.

Sex Drives Dimorphic Immune Responses to Viral Infections

“…The gene products of X or Y gene also facilitate epigenetic modifications on the DNA of an individual. SRY interacts with Kruppel-associated box (KRAB) domain transcriptional factor through the high mobility box (HMG) box on SRY to recruit histone-modifying enzymes such as histone deacetylase (HDAC) and heterochromatin protein 1, which remodels chromatin (99, 100). Few studies have evaluated sexual dimorphism in chromatin remodeling irrespective of hormonal influence and those that have, focused on the central nervous system.…”

Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters

“…The pEF1 SOX effector plasmids cloning strategy was previously published (52). Details for the various human pGL3 luciferase reporter constructs were also previously published (53).…”

“…All constructs were sequence confirmed using BigDye Sanger sequencing on an ABI 3130xl genetic analyzer (Applied Biosystems). The SRY-MAS electrophoresis mobility shift assay was performed as previously published (52).…”

“…Dissection of the Y chromosome elucidated the Sry gene as a candidate to elevate blood pressure in the rat (22,65). Part of the blood pressure elevation in the rat was due to changes in the RAS (19,40), a regulation that is seen by human SRY on human RAS promoters (52,53). Electroporation of Sry into the kidney of normotensive rats elevates plasma renin (REN) activity (19), an activity that is known to be elevated in human males relative to females (28).…”

“…Electroporation of Sry into the kidney of normotensive rats elevates plasma renin (REN) activity (19), an activity that is known to be elevated in human males relative to females (28). Evidence points to a combination of sex hormones and SRY regulating promoter activity of RAS genes, suggesting an elevation of the ACE/ANG II/AT1 axis and a depression of the ACE2/ANG-(1-7)/MAS axis (19,23,38,40,52,53). As SRY is primarily known for its role in testis determination (4), the regulation of the RAS and blood pressure was not initially expected.…”