Abstract
Long non-coding RNAs (lncRNA) are emerging as new genetic/epigenetic regulators that can impact almost all physiological functions. Here, we focus on the long non-coding steroid receptor RNA activator (SRA), including new insights into its effects on gene expression, the cell cycle, and differentiation; how these relate to physiology and disease; and the mechanisms underlying these effects. We discuss how SRA acts as an RNA coactivator in nuclear receptor signaling; its effects on steroidogenesis, adipogenesis, and myocyte differentiation; the impact on breast and prostate cancer tumorigenesis; and, finally, its ability to modulate hepatic steatosis through several signaling pathways. Genome-wide analysis reveals that SRA regulates hundreds of target genes in adipocytes and breast cancer cells and binds to thousands of genomic sites in human pluripotent stem cells. Recent studies indicate that SRA acts as a molecular scaffold and forms networks with numerous coregulators and chromatin-modifying regulators in both activating and repressive complexes. We discuss how modifications to SRA's unique stem-loop secondary structure are important for SRA function, and highlight the various SRA isoforms and mutations that have clinical implications. Finally, we discuss the future directions for better understanding the molecular mechanisms of SRA action and how this might lead to new diagnostic and therapeutic approaches.
Highlights
Recent analysis of numerous high-throughput mammalian genomic platforms suggests that protein-coding genes constitute only 2% of the genome, while many non-coding regulatory elements are transcribed into non-coding RNA [1,2,3,4,5,6]
In addition to its interaction with steroid receptors, we have further shown that human steroid receptor RNA activator (SRA) physically binds to and enhances transcriptional activities of a subset of nonsteroid nuclear hormone receptors, including murine thyroid hormone receptors (TRs) and steroidogenic factor 1 (SF-1), and human peroxisome proliferator-activated receptor-gamma (PPARγ)
We have shown that SRA is expressed in mouse embryonic stem cells and that Dax-1 augmentation of liver receptor homolog 1 (LRH-1)-mediated Oct4 activation is dependent upon SRA expression [61]
Summary
Recent analysis of numerous high-throughput mammalian genomic platforms suggests that protein-coding genes constitute only 2% of the genome, while many non-coding regulatory elements are transcribed into non-coding RNA (ncRNA) [1,2,3,4,5,6]. By site-directed mutagenesis and functional assays they determined that the distinct RNA motifs of SRA are important for its coactivation activity [43] These motifs include 11 topological substructures (STR 1–11) that are mainly located in the stemloop regions of the core sequence of human and mouse SRA. By using either ENCODE sequences or Ensemble data, and comparing the secondary structures of SRA RNA across vertebrates, it was revealed that evolutionary pressure preserves the RNA structural core in domains III and IV of SRA, rather than preserving the structure of SRAP itself [45, 49] This suggests that the primary functions of SRA1 predominantly relate to its lncRNA product, rather than those mediated via the SRAP protein. SRA can exist in both coactivator and corepressor complexes and has been linked to regulation of NR signaling, steroidogenesis, mesenchymal fate regulation, and other
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