Epigenetic Regulation of the Human Genome by Long Intergenic Non-coding RNAs (lincRNAs)
Ahmad M. Khalil, Ph.D.
Department of Genetics and Genome Sciences
Case Comprehensive Cancer Center
Case Western Reserve University School of Medicine
We previously discovered that the human genome encodes thousands of novel genes, which we refer to as long intergenic non-coding RNAs (lincRNAs). Recent studies have demonstrated important roles for lincRNAs in embryonic and organs development in vivo. Additionally, gene expression studies revealed that each lincRNA can regulate many protein-coding genes, either directly or indirectly, mostly at genomic sites far away from a lincRNA site of transcription, and thus, lincRNAs are thought to exert their effects in trans. The impact of lincRNAs on gene expression patterns has implicated lincRNAs in a wide range of critical biological functions including dosage compensation, genomic imprinting, alternative splicing, nuclear organization, and regulation of mRNA translation. Intriguingly, lincRNAs utilize various mechanisms to exert their effects in the cell. These mechanisms include acting as scaffolds to bind nuclear protein complexes and guide them to specific regions of the genome, serving as decoys that prevent transcription factors binding to DNA, and acting as microRNA “sponges.” Additional mechanisms are likely, but have yet to be fully elucidated.
Recently, there has been growing interest in unraveling the roles of lincRNAs in human disease with the hope that lincRNAs can be used as diagnostic biomarkers and/or therapeutic targets. In addition, there is increased focus on studying the functional roles of lincRNAs in cancer, since numerous lincRNAs have been shown to be dysregulated across multiple cancer types. These studies have also shown that the expression of some lincRNAs correlates with clinical parameters, such as overall patient prognosis and metastasis.
We have utilized several state of the art approaches to identify lincRNAs that contribute to cancer initiation, progression and metastasis with the long-term goal of developing RNA-based therapies. Thus far, we have identified lincRNAs that are dysregulated in Lung Cancer, Breast Cancer and Colon Cancer. We are following up on these exciting discoveries to determine the biological functions of top candidate lincRNAs, with the long-term objective of turning these discoveries into clinical tools (e.g., diagnostics) and therapeutic targets.
Background Review Article:
Niland, Courtney N., Callie R. Merry, and Ahmad M. Khalil. "Emerging roles for long non-coding RNAs in cancer and neurological disorders." Non-Coding RNA3 (2012): 25.