New Insights Into the Long Non-coding RNA SRA: Physiological Functions and Mechanisms of Action

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.

Long Non-coding RNA in Plants in the Era of Reference Sequences

“…However, some non-coding transcripts may arise from alternative splicing or truncation of first or last exons of protein coding genes. For example, SRA1 gene encodes for a lncRNA transcript [steroid receptor RNA activator (SRA)] as well as a protein coding transcript (SRAP) by alternative splicing (Sheng et al, 2018). Functional characterization of SRA have been performed well in both human and mouse (Nam et al, 2016).…”

Non-Coding RNAs in Breast Cancer: Intracellular and Intercellular Communication

“…SRA1 is unique in that not only does it encode lncSRA1s of different length [299], but SRA1 also encodes a protein: steroid receptor co-activator protein (SRAP) (reviewed in [300]). SRAP does not interact with the lncRNA SRA1 , but it interacts with NRs: ERα, androgen receptor (AR), and glucocorticoid receptor (GR), and is involved in splicing and cell cycle regulation [301]. The lncRNA SRA1 functions as a scaffold, and interacts with miRNA processing (DICER and TRBP) and RISC components, i.e., AGO2 and PACT; with other transcription factors, e.g., OCT4, NANOG, and FOXO1; and with chromatin modifiers and binding proteins, e.g., KMT2A (MLL1), KMT2D (MLL2), EZH2, and CTCF [301].…”

LncRNA Functions as a New Emerging Epigenetic Factor in Determining the Fate of Stem Cells

“…Furthermore, SRA can enhance insulin sensitivity by promoting cell cycling, inhibiting inflammatory gene expression and the TNFa-induced phosphorylation of c-Jun NH2-termianl kinase in pre-adipocytes. SRA −/− mice are lean with reduced adipogenic gene expression (Sheng et al, 2018). The lncRNA adipogenic differentiation-induced noncoding RNA (ADINR) is induced by adipogenesis and positively regulates both PPARγ and CEBPA expression by recruiting PA1 (a component of the MLL3/4 complex) to the CEBPA promoter and impacting H3K4me3 and H3K27me3 histone modification (Xiao et al, 2015).…”