Poster Presentation Hunter Cell Biology Meeting 2025

GWAS-empowered characterization of a long non-coding RNA gene as a sequence-based drug target in human type 2 diabetes using an in vivo nonhuman primate model (#127)

Leonard Lipovich 1 , Weizhong Wang 2 , Lanni Song 3 , Erica L. 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 Systems Biology, McGill University, Montreal, Canada
  5. Shenzhen Huayuan Biotechnology Co. Ltd., Shenzhen, China

In 2003, the Human Genome Project revealed that > 98% of the human genome sequence resided outside of protein-coding genes. Subsequently, in the FANTOM (Functional Annotation of Mammalian cDNA) and ENCODE (Encyclopedia of DNA Elements) Consortia, we demonstrated that over two-thirds of the ~75,000 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 are versatile, both positive and negative, epigenetic and post-transcriptional, regulators of protein-coding genes. We previously described primate-specific lncRNAs in epilepsy and cancer [4,5]. Interrogating the genomewide intersection of significant disease-associated genetic variants from Genome-Wide Association Studies (GWAS) with lncRNA genes, we identified 475 lncRNAs as putative 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 carrying 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 suitable liver-specific target for RNAi-based T2D treatments. Its knockdown in vivo reduces fasting glucose levels and normalizes liver glycogen storage, concomitant with decreased HbA1c and cholesterol levels. Analysis of ~100 additional lncRNAs from T2D GWAS is ongoing. We conclude that human lncRNA genes with recent evolutionary origins in primates contribute to disease etiologies as an important class of druggable targets.

  1. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Gonzalez D, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez J, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard T, Notredame C, Harrow J, and Guigó R. The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Research 22: 1775-1789, 2012.
  2. Engström PG, Suzuki H, Ninomiya N, Akalin A, Sessa L, Lavorgna G, Brozzi A, Luzi L, Tan SL, Yang L, Kunarso G, Ng E, Batalov S, Kai C, Kawai J, Carninci P, Hayashizaki Y, Wells C, Bajic VB, Orlando V, Reid JF, Lenhard B, and Lipovich L. Complex loci in human and mouse genomes. PLoS Genetics 2(4):e47 , 2006.
  3. Wood EJ, Chin-Inmanu K, Jia H, and Lipovich L. Sense-antisense gene pairs: sequence, transcription, and structure are not conserved between human and mouse. Frontiers Genet. 4: 183 , 2013.
  4. Kirchner A, Dachet F, Lipovich L, and Loeb JA. Activity-Dependent Non-Coding RNA MAPK Interactome of the Human Epileptic Brain. Non-Coding RNA 9(1): 3, 2023.
  5. Lin CY, Kleinbrink EL, Dachet F, Cai J, Ju D, Goldstone A, Wood EJ, Liu K, Jia H, Goustin AS, Kosir MA, Thepsuwan P, and Lipovich L. Primate-specific oestrogen-responsive long non-coding RNAs regulate proliferation and viability of human breast cancer cells. Open Biol. 6: 12 , 2016.
  6. Manning AK, Goustin AS, Kleinbrink EL, Thepsuwan P, Cai J, Ju D, Leong A, Udler MS, Brown JB, Goodarzi MO, Rotter JI, Sladek R, Meigs JB, and Lipovich L. A Long Non-coding RNA, LOC157273, Is an Effector Transcript at the Chromosome 8p23.1-PPP1R3B Metabolic Traits and Type 2 Diabetes Risk Locus. Frontiers in Genetics doi: 10.3389/fgene.2020.00615, 2020.