Oral Presentation Australasian RNA Biology and Biotechnology Association 2024 Conference

GWAS-empowered characterization of a primate-specific long non-coding RNA gene as a causal contributor to, and a sequence-based drug target in, human type 2 diabetes: insights from a nonhuman primate model (108247)

Leonard Lipovich 1 , Weizhong Wang 2 , Lanni Song 3 , Erica Kleinbrink 4 , Xiaosong Zhang 5
  1. Wayne State University, Detroit, MICHIGAN, United States
  2. Shenzhen Huayuan Biotechnology Co. Ltd., Shenzhen, China
  3. College of Science, Mathematics, and Technology, Wenzhou-Kean University, Wenzhou, China
  4. Quantitative Life Sciences, McGill University, Montreal, Canada
  5. Shenzhen Huayuan Biotechnology Co. Ltd., Shenzhen, China

Over two decades ago, the Human Genome Project revealed that 98% of the human genome sequence resided outside of protein-coding genes. In the FANTOM (Functional Annotation of Mammalian cDNA) and ENCODE (Encyclopedia of DNA Elements) Consortia, we demonstrated that two-thirds of the ~60,000 human genes do not encode proteins, and that most human long non-coding RNA (lncRNA) genes lack evolutionary conservation beyond primates [1-3]. LncRNA genes are now recognized as the most abundant class of human non-coding RNA genes. An order of magnitude more abundant than microRNAs, lncRNAs possess protean versatility as positive and negative, epigenetic and post-transcriptional regulators. We previously described primate-specific lncRNAs in epilepsy and cancer [4,5]. Interrogating the genomewide interface of significant disease-associated genetic variants from Genome-Wide Association Studies (GWAS) with promoters and exons of lncRNA genes, we identified 475 lncRNAs implicated by genetic evidence as causal contributors to common diseases, including type 2 diabetes. We manually annotated, and functionally validated in the laboratory, the primate-specific lncRNA LOC157273 [6], which - when it contains the disease-risk allele of the exon 2 SNP rs4841132 - causes high fasting glucose levels by suppressing its neighbor gene PPP1R3B (which converts blood glucose into liver glycogen), as a direct T2D causal candidate. We described gene structure differences of the human and Macaca fascicularis orthologs of LOC157273 and tested 2 siRNA-based drug candidates for safety and non-toxicity in this animal model, demonstrating that LOC157273 is a liver-specific target for RNAi-based T2D treatments. Its knockdown in vivo reduces fasting glucose levels and rescues liver glycogen storage, concomitant with decreased HbA1c and cholesterol levels. Analysis of ~100 additional primate-specific lncRNAs from manual reannotation of T2D GWAS hits is ongoing. We conclude that human lncRNA genes with recent evolutionary origins in primates contribute to disease etiologies and represent an important class of druggable targets.

 

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