title: Research resource: expression profiling reveals unexpected targets and functions of the human steroid receptor RNA activator (SRA) gene.
abstract: The human steroid receptor RNA activator (SRA) gene encodes both noncoding RNAs (ncRNAs) and protein-generating isoforms. In reporter assays, SRA ncRNA enhances nuclear receptor and myogenic differentiation 1 (MyoD)-mediated transcription but also participates in specific corepressor complexes, serving as a distinct scaffold. That SRA RNA levels might affect some biological functions, such as proliferation, apoptosis, steroidogenesis, and myogenesis, has been reported. However, the breadth of endogenous target genes that might be regulated by SRA RNAs remains largely unknown. To address this, we depleted SRA RNA in two human cancer cell lines with small interfering RNAs and then assayed for changes in gene expression by microarray analyses. The majority of significantly changed genes were reduced upon SRA knockdown, implicating SRA RNAs as endogenous coactivators. Unexpectedly, only a small subset of direct estrogen receptor-alpha target genes was affected in estradiol-treated MCF-7 cells. Eight bona fide SRA downstream target genes were identified (SLC2A3, SLC2A12, CCL20, TGFB2, DIO2, TMEM65, TBL1X, and TMPRSS2), representing entirely novel SRA targets, except for TMPRSS2. These data suggest unanticipated roles for SRA in glucose uptake, cellular signaling, T(3) hormone generation, and invasion/metastasis. SRA depletion in MDA-MB-231 cells reduced invasiveness and expression of some genes critical for this process. Consistent with the knockdown data, overexpressed SRA ncRNA coactivates certain target promoters and may enhance the activity of some coregulatory proteins. This study is a valuable resource because it represents the first genome-wide analysis of a mammalian RNA coregulator.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Foulds
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: Weiwen
authors.initials: W
authors.lastname: Long
authors.forename: Andrew
authors.initials: A
authors.lastname: Le
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D051274:Glucose Transporter Type 3 / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D022661:RNA, Untranslated / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D051274:Glucose Transporter Type 3; D007453:Iodide Peroxidase; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D000097564:Iodothyronine Deiodinase Type II; C405423:steroid receptor RNA activator