IEEE BIBM 2024 Workshop on Long Non-Coding RNAs: Mechanism, Function, and Computational Analysis (BIBM-LncRNA)

Title: LncRNAs and Human SARS-CoV-2 Interactions

Abstract:

Brief Bio: Dr. Enguita is holding a position of Assistant Professor and Senior Investigator at the Faculty of Medicine in the University of Lisbon. His research interest has been evolved during his training as scientist and teacher. His PhD was focused on the genetic and biochemical characterization of specific biosynthetic pathways of beta-lactam antibiotics in filamentous bacteria. He complemented by basic knowledge in molecular biology with a long post-doctoral training in structural biology, that allow him to conduct his first research laboratory as a group leader focused on hostpathogen interactions. His transversal scientific training was also expanded to a more clinically oriented facet, currently exemplified by his ongoing research projects in non-coding RNAs and cardiovascular diseases. His scientific knowledge in diverse and interconnected areas, allows him to analyze and dissect the biological problems with an integrative point of view combining different techniques and approaches. Currently, his research laboratory is interested in the characterization of the functions of non-coding RNAs (namely circRNAs, lncRNAs and miRNAs) in different chronic cardiovascular conditions. His group has gained extensive experience in the use of highthroughput technologies for the characterization of the genome dynamics, applied to the dissection of genotypephenotype relationships in human chronic diseases. Moreover, he also exploits his previous knowledge of structural biology to target relevant biomolecules for disease (proteins and RNAs) by using rational drug design methods (computer-aided drug design, molecular modelling, and molecular dynamics).

Title: Coding and Non-coding LncRNAs in Hepatocellular Carcinoma

Abstract:

Brief Bio: Dr Puri Fortes received a BS degree in Biological Sciences from the University of Navarra, Spain in 1990, and a D. in Sciences from the Universidad Autonoma de Madrid, Spain in 1994. She has carried out research stays at the European Molecular Biology Laboratory (EMBL. Heidelberg). Since 1999 she has been working as PI at the University of Navarra, and since 2004 she has been a member of the CIMA University of Navarra. Dr Fortes is a is co-inventor on 6 patents, and has participated in a clinical trial. She has also participated in 40 research projects, being principal investigator in 20 of them. She has participated in competitive projects funded by: European Union, Ministry of Ministry of Science and Innovation, Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Government of Navarra and private organizations. Her research interests include identification and analysis of long non-coding RNAs related to hepatocellular carcinoma, selection of functional RNAs for the upregulation and regulation of gene expression, identification of cancer microproteins expressed from lncRNAs, adenoviral microRNAs, and microRNAs in gene therapy. She has participated in the publication of about 90 scientific articles in international journals and in more than 150 communications to national/international congresses. She has also participated in several agreements with companies for research development and co-development.

Title: GWAS-driven characterization of primate-specific long non-coding RNA genes as causes of, and sequence-based drug targets in, cancer and diabetes

Abstract: Over two decades ago, the Human Genome Project revealed that 98% of the human genome sequence resided outside of protein-coding genes. Through our early contributions to the FANTOM (Functional Annotation of Mammalian cDNA) and ENCODE (Encyclopedia of DNA Elements) Consortia, we helped to demonstrate 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. Long non-coding RNA (lncRNA) genes are now recognized as the most abundant, albeit still poorly understood, class of human non-coding RNA genes, eclipsing the earlier-characterized microRNAs in numbers by an order of magnitude, as well as in their protean versatility as positive and negative, global and targeted, epigenetic and post-transcriptional regulators of disease networks. We characterized 20 primate-specific, estrogen-induced oncogenic (and estrogen-repressed tumor-suppressor) lncRNAs in human estrogen receptor positive breast cancer. Suppression and rescue, respectively, of these lncRNAs provide new paths toward cancer treatment. Interrogating the global interface of significant disease-associated genetic variants from Genome-Wide Association Studies (GWAS) and the promoters and exons of lncRNA genes, we identified 475 lncRNAs strongly implicated by genetic evidence as causal contributors to common diseases, including type 2 diabetes. We manually annotated, and mechanistically validated in the laboratory, the primate-specific lncRNA LOC157273, which - when it carries the disease-risk allele of the exon 2 SNP rs4841132 - causes high fasting glucose levels by suppressing its neighbor gene PPP1R3B (responsible for the conversion of blood glucose into glycogen stored in the liver), as a direct T2D causal candidate. We described the gene structure differences of the human and Macaca fascicularis orthologs of this gene and successfully tested 3 siRNA-based drug candidates for safety and nontoxicity in this animal model, demonstrating LOC157273 as a liver-specific target for RNAi-based drugs. Its knockdown in vivo in the monkey reduces blood glucose levels, rescues liver glycogen storage, and is accompanied by decreased HbA1c and cholesterol levels. Across our cancer and diabetes projects, we conclude that human lncRNA genes with recent evolutionary origins, lacking conservation beyond primates, are contributing to disease etiologies and represent an important novel class of druggable targets.

Brief Bio: Leonard Lipovich is an internationally recognized pioneer in long non-coding RNA (lncRNA) biology of human disease. He built the first published catalog of human lncRNA genes supported by full-length experimental data. Leading a platform effort within the ENCODE (Encyclopedia of DNA Elements) Consortium -- a direct successor to the Human Genome Project -- Prof. Lipovich was the first to empirically reveal unexpected ribosomal translation of short open reading frames from lncRNAs in human cells using mass spectrometry. His work has been fundamental to establishing that primate-specific lncRNAs in humans directly contribute to the etiology of human diseases, including cancer, diabetes, and epilepsy. His current focus is on identifying, and validating in the laboratory, lncRNAs from genome-wide association studies and personalized genome sequencing, as well as from in-vivo transcriptome analysis and high-throughput screens, as druggable causes of those diseases.

Leonard Lipovich earned his B.A. (cum laude) in Genetics and Development from Cornell University (1998), and his Ph.D. in Molecular Biotechnology from the Department of Genome Sciences at the University of Washington, Seattle (2003). He completed postdoctoral training at the Genome Institute of Singapore, where he characterized the first mammalian lncRNA functional in stem cell pluripotency and discovered the prevalence of primate-specific lncRNAs in sense-antisense gene pairs. Dr. Lipovich joined Wayne State University in Detroit, Michigan, USA in 2007, as an assistant professor, attaining an associate professorship and tenure in 2013, then a full professorship in 2019. In 2024, he transitioned to Wenzhou-Kean University in Wenzhou, China. He is active in lncRNA-based drug development efforts, through commercialization projects with startup RNA-biotech companies in China and elsewhere.

Dr. Lipovich received the U.S. National Institutes of Health (NIH) Director's New Innovator Award for the 2014-2019 project cycle. In 2015, he chaired both the Keystone Symposium and the Royal Society international scientific meeting on lncRNA. To date, Dr. Lipovich (h-index: 46) has published 91 peer-reviewed papers (including 38 as a first, last, or principal author), delivered over 50 invited presentations, and chaired numerous sessions at key conferences. Dr. Lipovich is a Founding Co-Chair (2019-present) of the annual LncRNA Workshop at the IEEE-BIBM conference. His goal is to improve human health through personalized, lncRNA-targeted post-genomic therapeutics.

Title: HPV-16 Increases Expression of Long Non-coding Circular RNA circIGF2BP3 to Influence Cervical Cancer Progression

Abstract: Human Papillomavirus (HPV) has long been known to cause different types of cancers, namely squamous cell carcinomas, of the head, neck and cervix. The high-risk HPV type 16(HPV16) is responsible for a majority of HPV-related cancers. It has recently been discovered that specific non-coding RNAs (ncRNAs) can contribute to tumor proliferation, angiogenesis, and metastasis. Circular RNAs (circRNAs) are a highly stable, closed-loopRNA molecules that have recently been shown to contribute to oncogenesis. A recent publication identified a circular ncRNA that originates from a back-splicing event between exons 4 and 13 of Insulin-like Growth Factor 2 Binding Protein 3 (IGF2BP3) mRNA, known as circIGF2BP3 (hsa_circ_0079587) in Non-Small Cell Lung Cancer. Our group conducted a global circRNA expression Microarray in primary cervical keratinocytes, containing theHPV16 genome as an episome, to identify differentially expressed circRNAs upon HPV infection. Interestingly, circIGF2BP3 was found to be significantly overexpressed in HPV16+cell lines, which led us to hypothesize that overexpression of circIGF2BP3 by HPV16 has a role in tumorigenesis. In screening HPV16+ cell lines, Cerv-186 and Caski were found to have the highest expression of this circRNA. To examine the function of circIGF2BP3, we designed an siRNA complementary to the joined 5' and 3' ends of circIGF2BP3. Specificity to circIGF2BP3 was verified via qRT-PCR and Western blotting for linear IGF2BP3 mRNA and protein, respectively. We then performed functional assays with the circIGF2BP3 knockdown-- including Transwell Migration, Cell Proliferation, and Senescence Assays. We showed absence of circIGF2BP3 is associated with a decrease in cervical cancer cell migration, and an increase in cell proliferation. CircIGF2BP3 is a novel circRNA with important implications for the progression of HPV16+ cervical cancer.

Brief Bio: Dr. Ivan Martinez is an Associate professor at WVU Cancer Institute and the Department of Microbiology, Immunology and Cellular Biology at WVU. Originally from Mexico City, he graduated with honors form the most important university in Mexico: The National Autonomous University of Mexico. He completed his Ph.D. in Molecular Genetics and Biochemistry at the University of Pittsburgh, and continued his training as a postdoctoral fellow in the Department of Genetics at Yale University School of Medicine for over 5 years. After his training, he was recruited at WVU in 2013. The goal of Dr. Martinez research is to understand the importance of a group of molecules called non-coding RNAs in different types of cancers such as cervical cancer, head and neck cancer, and lung cancer as well as viral infections.