From Discovery to Function: The Expanding Roles of Long NonCoding RNAs in Physiology and Disease

Abstract

Long noncoding RNAs (lncRNAs) are a relatively poorly understood class of RNAs with little or no coding capacity transcribed from a set of incompletely annotated genes.They have received considerable attention in the past few years and are emerging as potentially important players in biological regulation.Here we discuss the evolving understanding of this new class of molecular regulators that has emerged from ongoing research, which continues to expand our databases of annotated lncRNAs and provide new insights into their physical properties, molecular mechanisms of action, and biological functions.We outline the current strategies and approaches that have been employed to identify and characterize lncRNAs, which have been instrumental in revealing their multifaceted roles ranging from cis-to trans-regulation of gene expression and from epigenetic modulation in the nucleus to posttranscriptional control in the cytoplasm.In addition, we highlight the molecular and biological functions of some of the best characterized lncRNAs in physiology and disease, especially those relevant to endocrinology, reproduction, metabolism, immunology, neurobiology, muscle biology, and cancer.Finally, we discuss the tremendous diagnostic and therapeutic potential of lncRNAs in cancer and other diseases.(Endocrine Reviews 36: 25-64, 2015) I. Introduction II.Defining LncRNAs A. An evolving definition of lncRNAs B. A working definition of lncRNAs III.Identifying and Cataloging LncRNAs A. Identification of lncRNA transcripts: omics approaches B. Evaluation of coding potential C. Gene-specific validations D. Cataloging lncRNAs in public databases IV.Functional Characterization of LncRNAs A. Expression profiling across spatial and temporal gradients B. Coding-noncoding coexpression relationships: guilt-by-association C. A role for lncRNAs in the cis-regulation of gene expression D. A role for lncRNAs in the trans-regulation of gene expression E. LncRNA-protein interactions drive molecular outcomes in cis and trans gene regulation F. Methods for the detection of lncRNA interaction sites across the genome G. Beyond the nucleus: a broader view of lncRNA functions V. Lessons Learned From the Best-Characterized LncRNAs A. XIST B. MALAT1 C. HOTAIR VI.The Biology of LncRNAs in Endocrine-Related Systems A. LncRNAs and hormonal signaling: regulators, coregulators, and modulators of steroid receptors B.