SAT-007 The Long Non-coding RNA Gas5 Selectively Regulates Corticosteroid Receptor Activity

Abstract

Gas5 is a long non-coding RNA initially identified as a factor inducing cell growth arrest and apoptosis. Several stem-loop structures in Gas5 3’-terminal sequence mimic hormone response elements (HRE) with different binding affinities towards estrogen, glucocorticoid and mineralocorticoid receptors. Based on this property, Gas5 acts as a decoy for steroid nuclear receptors, competing with genomic HREs and downregulating receptor activity. In this study we asked whether Gas5 is an aldosterone-regulated gene in vivo and studied its effect on mineralocorticoid and glucocorticoid receptor activity (MR and GR). Our results show that Gas5 is expressed in the rat distal colon epithelium and its abundance increased after four days of low Na+ diet in an MR-dependent fashion. In addition, MR transfected in HEK293 cells regulates Gas5 expression in response both to aldosterone and cortisol. Co-expression of Gas5 with either MR or GR in COS-7 cells confirmed previous findings showing that it decreases receptor-mediated transactivation. However, when both MR and GR where co-expressed, Gas5 reduced cortisol- but not aldosterone-dependent reporter gene transactivation. This effect does not depend on alterations of receptor expression, nuclear translocation or dimerization, but can be ascribed to differential affinities in MR and GR binding to Gas5. Our results suggest a role for Gas5 selectively regulating corticosteroid signaling in the rat colon.