Sign In

“Long Non-Coding RNA (LncRNA) Genes Are Druggable Causes of Human Diseases.”

Virtual - MS Teams 17 FEB 20212 PM

"Long Non-Coding RNA (LncRNA) Genes Are Druggable Causes of Human Diseases."

By Prof. Leonard Lipovich

Professor, Basic Medical Sciences Department, College of Medicine,
Mohammed Bin Rashid University, Dubai, UAE.

 

Date/Time:  Wednesday, February 17, 2021 at 2:00PM
Venue: MS Teams: Click here to join the meeting

 

Abstract:

The Central Dogma of Molecular Biology, which stipulates that information flows from DNA, through RNA, to proteins, relegated ribonucleic acid (RNA) to the sidelines during the last century, as mainly a humble messenger (mRNA) bridging genes to proteins. This cameo role in the textbook narrative belies the centrality of RNA to all life: the RNA World Hypothesis posits that, in the "primordial soup" after the origin of life on Earth, an ancient world of self-replicating RNA molecules pre-dated the rise of familiar, DNA-based life forms. In the post-COVID period of the post-genomic era, RNA has become a household word: a virus with an RNA genome is devastating the world, before its hoped-for containment by mRNA biopharmaceuticals (vaccines).

Launched upon completion of the Human Genome Project in 2003, the FANTOM (Functional Annotation of Mammalian cDNA) and ENCODE (Encyclopedia of DNA Elements) consortia, to which I prominently contributed, brought RNA biology forward from the dawn of life into 21st-centry medicine. Our work revealed that two-thirds of the 60,000 human genes, residing in "junk DNA," do not encode proteins, but instead, yield non-messenger RNA molecules with fundamental, unexpectedly diverse roles in normal cellular processes and in disorders ranging from diabetes and cardiovascular disease to cancer and autoimmunity. We showed that these lncRNA genes in humans, including those regulated by estrogen and contributing to breast cancer progression, often lack evolutionary conservation beyond primates; hence, lncRNAs clearly have biological functions in the absence of deep conservation, while non-primate models, such as mouse, are unsuitable for loss-of-function studies of lncRNA genes' non-existent orthologs. The resultant understanding of RNA mechanisms has facilitated the emergence of artificial RNAs as blockbuster drugs: from the synthetic RNA Miravirsen, an early treatment of hepatitis C virus infection that targets the interaction between the virus' RNA genome and the host microRNA-122, to the $10billion PCSK9 inhibitor Inclisiran, approved in late 2020 as a new RNAi treatment for hypercholesterolemia.

Over 95% of significant disease-associated variants from Genome-Wide Association Studies (GWAS) are non-coding, but the GWAS field historically focused on protein-coding candidates. There is now an emergent conceptual shift from viewing genetic variants as mere markers to understanding them as direct contributors to disease etiologies. Overlapping all public significant GWAS variants with all lncRNA exons, we identified, as a top hit, LOC157273, a primate-specific cytoplasmic lncRNA, expressed solely in hepatocytes, and independently seen (but uniformly mis-annotated) in over 20 GWAS of type 2 diabetes, body mass index, cholesterol and triglyceride levels, cardiovascular disease, and obesity. We show this lncRNA to be a negative regulator of liver glycogen storage, and that, hence, it may contribute to higher fasting-glucose levels in vivo. We have developed, and validated in-vitro, oligonucleotide-based drugs targeting this lncRNA in primary human hepatocyte culture, where the treatment rescues healthy levels of glycogen deposition. In view of the feasibility of targeting liver ncRNAs with sequence-based drugs, we posit that sequence-based RNAi drugs targeting our lncRNA – and dozens of other liver-expressed lncRNAs identified by our manual UCSC Genome Browser-assisted reannotation of public T2D and CVD GWAS data – can be delivered to the liver for precision-medicine treatments, tailored to those patients whose disease progression is caused in part by the disease alleles of those lncRNA genes. Our new initiatives here aim to explore and target the non-coding components of the genetic basis of T2D, CVD, and metabolic disease susceptibility here in the UAE.


Brief Biography:

Leonard Lipovich earned his B.A. (cum laude) in Genetics and Development from Cornell University (1998), and his Ph.D. in Genome Sciences from the University of Washington, Seattle (2003). He focuses on long non-coding RNA (lncRNA) genes, the most abundant -
but the least well-understood - class of human non-protein-coding RNAs. He completed
postdoctoral training at the Genome Institute of Singapore, where he discovered the first
mammalian lncRNA functional in stem cell pluripotency and led an international effort that
highlighted the prevalence of evolutionarily non-conserved, primate-specific lncRNAs
in human sense-antisense gene pairs. He is fascinated by the role of these primate-specific
lncRNAs in primate behavioral and cognitive complexity as well as in human disease.
Dr. Lipovich joined Wayne State University in Detroit, Michigan, as an assistant professor in 2007. Working within the ENCODE (Encyclopedia of DNA Elements) Consortium, which succeeded the Human Genome Project, he was the first to examine lncRNA translation in human cells using mass spectrometry, showing that most lncRNAs are not translated. In 2014, after being promoted to an associate professorship with tenure, Dr. Lipovich received the U.S. National Institutes of Health (NIH) Director's New Innovator Award (a $2,300,000 grant) to study primate-specific lncRNAs in human cancer. His current project is developing RNA-based therapeutics against a liver lncRNA target that he discovered from Genome-Wide Association Studies and validated in his laboratory as a novel cause of type 2 diabetes and diverse metabolic diseases. He has chaired two highly prestigious conferences: a Keystone Symposium on lncRNA, and the only Royal Society International Scientific Meeting ever devoted to this topic. To date, Dr. Lipovich has published over 65 peer-reviewed papers and has delivered over 50 talks at major conferences and as invited seminars. In 2020, Dr. Lipovich moved to the Mohammed Bin Rashid University of Medicine and Health Sciences in Dubai, United Arab Emirates, where he is a professor in the Department of Basic Medical Sciences, College of Medicine. His long-term goal is to improve human health through personalized, lncRNA-targeted therapeutics.

 




Back to list