IEEE BIBM 2022 Workshop on Long Non-Coding RNAs: Mechanism, Function, and Computational Analysis (BIBM-LncRNA)

Title: Evolution, functions, and modes of action of long noncoding RNAs.

Abstract: It is now clear that many intergenic regions in eukaryotic genomes give rise to a range of processed and regulated transcripts that do not appear to code for functional proteins. A subset of these are long (>200 nt), capped, and polyadenylated RNAs transcribed by RNA polymerase II and collectively called long noncoding RNAs (lncRNAs). The recent estimates are that the human genome may have >50,000 distinct lncRNA-producing loci, many of which show tissue-specific activity and dysregulation in human disease, including cancer and neurodegeneration.

Given the growing number of lncRNAs implicated in human disease or required for proper development, fundamental questions that need to be addressed are: Which lncRNAs are functional? How is functional information encoded in the lncRNA sequence? Is this information interpreted in the context of the mature or the nascent RNA? What are the identities and functional roles of specific sequence domains within lncRNA genes? These are challenging questions, primarily because of the substantial heterogeneity in mechanisms utilized by lncRNAs and the current paucity of lncRNAs with well-understood mechanisms. We are tackling these questions by combination of experimental methods with a focus on lncRNA functions in early cell fate decisions and computational methods focused on lncRNA evolution. I will describe our efforts to decode conserved combinations of short functional sequence elements in lncRNAs, with a particular focus on the Chaserr/Chd2 axis.

Brief Bio: Prof. Igor Ulitsky earned a BSc in Computer Science and Life Sciences (2004) and a PhD in Computer Science (2009) at Tel Aviv University. He studied as a postdoctoral fellow at Whitehead Institute for Biomedical Research in Cambridge, MA and joined the Weizmann Institute in 2013, where his lab studies the functions and modes of action of long noncoding RNAs, and the post-transcriptional fate of all long RNA molecules. Prof. Ulitsky has been awarded a number of academic honors, including the Blavatnik Award for Young Scientists in Life Sciences (2020), the RNA Society Early Career award (2020), an EMBO Young Investigator Award (2016), an ERC starting and consolidator grants (2015 and 2020), and Alon Fellowship (2014).

Title: Deciphering roles for lncRNAs in human brain activity, disease, and death

Abstract: The human brain has evolved to generate extraordinary capabilities enabling complex behaviors not present in other species. Due to their more rapid rate of evolution, lncRNAs have a significant potential to contribute to the uniqueness of the human brain through a wide variety of functions that are still poorly understood. At the same time, and perhaps because of these capabilities, the human brain suffers from a number of diseases related to both too much brain activity (epilepsy) and too little (neurodegeneration). Given these strong evolutionary differences, a major challenge in deciphering the roles of lncRNAs in human brain function and disease comes from a critical need to study them in the human brain rather than other species.

Patients who suffer from epileptic seizures can obtain significant improvements by removing portions of their brains. Epileptic electrical networks in fact are often quite large and complex often requiring very large portions of the brain to be removed surgically in both children and adults. In order to make critical decisions about which portions to remove and which to leave intact, extensive long-term electrical recordings are performed in vivo. When precisely localized to the electrical recordings, the brain tissues removed from these surgical procedures offer a rare opportunity to explore differences in human brain regions with abnormal and normal brain activity. We have taken a multi-systems approach to study these priceless tissues linking genomic, proteomic, and molecular differences to quantitative electrical activities, brain imaging studies, and clinical data through a relational database. In this talk, I will summarize our findings on lncRNA expression and function as they relate to human brain activity with a specific interest in how a subset of lncRNAs within the MAPK signaling cascade contribute. Unlike epilepsy, where we have access to freshly isolated human brain, for most other human brain diseases including Alzheimer’s disease, we have to wait until death to collect tissues for research. When comparing the genomic landscape between fresh human brain samples and postmortem samples, we discovered marked differences in coding and non-coding gene expression suggesting that dead brain is not entirely dead. While neuronal genes involved in brain activity are rapidly degraded, other cells and ‘zombie genes’ come to life making the interpretation of postmortem human brain genomic studies challenging.

Brief Bio: Dr. Loeb is a practicing neurologist, epileptologist and neuroscientist who currently holds the John S. Garvin Chair, Professor and Head of the Department of Neurology and Rehabilitation. He received his A.B. in Chemistry, M.D. and PhD. from the University of Chicago. After completed a residency in Neurology at the Massachusetts General Hospital in Boston, he joined the faculty of Harvard Medical School where he also had fellowship training in epilepsy at Harvard's Beth Israel Deaconess Hospital. Dr. Loeb conducted postdoctoral work in the Department of Neurobiology at Harvard Medical School with Dr. Gerald Fischbach where he became interested in how understanding early neural development can teach us what goes wrong in human disease and suggest new treatments. This and other work focusing on translating basic discoveries into new treatments has resulted in high profile publications, federal and foundation grants support, and a number of patents, including one for a targeted drug that blocks neuregulin signaling and shows promise in degenerative disease that blocks neural inflammation, such as ALS and Alzheimer’s. His work in treating epilepsy patients led to a one-of-a-kind large-scale, systems biology project of human brain tissues that links the genes, molecular and cellular signals that underlie the abnormal electrical activities that characterize this common neurological disorder. Dr. Loeb is director of the University of Illinois NeuroRepository, director of biomedical informatics in UIC’s Center for Clinical and Translational Science, and Chief Clinical Strategist for the Sturge-Weber Foundation. To build on his scientific efforts and translate discoveries back to patients through public-private partnerships, he recently formed ‘I-BRAIN’ (Illinois Brain Analytics) in close collaboration and with support from the Discovery Partners Institute.

Title: About Chomsky, patterns, non-codingRNAs and cancer therapy.

Abstract: The world of noncoding RNAs (ncRNAs) is composed of an enormous and growing number of transcripts, ranging in length from tens of bases to tens of kilobases, involved in all biological processes and altered in expression and/or function in many types of human disorders. The premise of this review is the concept that ncRNAs, like many large proteins, have a multidomain architecture that organizes them spatially and functionally. As ncRNAs are beginning to be imprecisely classified into functional families, we review here how their structural properties might inform their functions with focus on structural architecture-function relationships. We will describe the properties of "interactor elements" (IEs) involved in direct physical interaction with nucleic acids, proteins, or lipids and of "structural elements" (SEs) directing their wiring within the "ncRNA interactor networks" through the emergence of secondary and/or tertiary structures. We suggest that spectrums of "letters" (ncRNA elements) are assembled into "words" (ncRNA domains) that are further organized into "phrases" (complete ncRNA structures) with functional meaning (signaling output) through complex "sentences" (the ncRNA interactor networks). This semiotic analogy can guide the exploitation of ncRNAs as new therapeutic targets through the development of IE-blockers and/or SE-lockers that will change the interactor partners' spectrum of proteins, RNAs, DNAs, or lipids and consequently influence disease phenotypes.

Brief Bio: George Adrian Calin received both his M.D. and PhD. degrees at Carol Davila University of Medicine in Bucharest, Romania. After working cytogenetics as undergraduate student with Dr. Dragos Stefanescu in Bucharest, he completed a cancer genomics training in Dr. Massimo Negrini’s laboratory at University of Ferrara, Italy. In 2000 he became a postdoctoral fellow at Kimmel Cancer Center in Philadelphia, PA, and while working in Dr. Carlo Croce laboratory Dr. Calin was the first to discover the link between microRNAs and human cancers, a finding considered as a milestone in microRNA research history. He is presently a Professor in Experimental Therapeutics and Leukemia Departments at M. D. Anderson Cancer Center in Houston and studies the roles of microRNAs and other non-coding RNAs in cancer initiation and progression and in immune disorders, as well as the mechanisms of cancer predisposition linked to non-codingRNAs. Furthermore, he explores the roles of body fluids miRNAs as potential hormones and biomarkers, as well as new RNA therapeutic options for cancer patients. Simply, he is having fun making discoveries and publishing and, from time to time, getting funded grants!

Title: GWAS and Genome Epidemiology OF LncRNA Variants: COVID- 19

Abstract: In recent years, more and more data have appeared that most GWAS hits fall in non-coding regions of the genome and long non-coding RNAs (lncRNAs) are emerging as drivers of different diseases. Tens of thousands of long noncoding RNA (lncRNA) genes regulated activity of protein-coding genes in various tissues and their response to the environment influences. Nevertheless, their disease contributions, and druggability potential, remain poorly understood. We hypothesize that a proportion of risk SNPs identified by GWAS coincide with regulatory non-coding RNA species, such as long non-coding RNAs (lncRNAs). Using the example of GWAS COVID-19 studies, the role of SNPs in genes of long non-coding RNAs was investigated. We used data from COVID GWAS v4 (genome-euro.ucsc.edu) and COVID19-hg GWAS meta-analyses round 5 (www.covid19hg.org). We examined all SNPs for possible localization in lncRNA, and also conducted a survey of all possible lncRNA genes located closer than 50 kb of each variant SNP were mapped in COVID GWAS. Maps of interactions for RNA identified in version 5 for lncRNAs (IL10RB-AS1, MGC57346, CCR5AS) with miRNA and coding protein genes were built. Using the LncRRIsearch web server (www.rtools.cbrc.jp/LncRRIsearch), we predicted interactions between the miRNAs of highlighted genes and various lncRNAs. Then we analyzed SNPs in the genes encoding proteins and studied the lncRNAs that could interact with them. For example, in the TYK2 (tyrosine kinase) gene, we identified three lncRNAs that showed the highest probability of interaction with it: RP11-573D15.8-01, AP006621.9-001, and RP11-95O2.5-001. Each of these lncRNAs interacts with more than 15 different miRNAs. Тhe discovery of ways of regulating gene activity lncRNAs and their relationship with each other will make it possible to assess the norm of reaction of the genotype, and serves as an approach to personalized medicine.

Brief Bio: TatIana Shkurat, Doctor of Biological Sciences, Professor, is the Head of the Genetics Department at the Southern Federal University (Rostov-on-Don, Russian Federation). She is PI and group leader at her home institution. She has extensive experience in supervising research teams and training doctoral candidates, and has led more than 30 grant-funded research projects in Russian as well as internationally sponsored projects. She has developed extensive intellectual property (IP), having been granted patents on: methods of gene diagnostics of monogenic and multifactorial diseases, certificates of the computer program for automatic search of motifs and visual analysis of images of nucleotide sequences. Recently, Prof. Shkurat has focused on the interface of non-coding DNA/RNA, evolutionary genomics, and personalized medicine. Her preliminary results represent a significant advance toward the future deployment of approaches for the validation and utilization of novel therapeutic targets in patients with different diseases, based on lncRNA and genome editing.

Title: NcRNAs in Sports Medicine

Abstract: Non-coding RNAs (ncRNAs) participate in the orchestration of gene expression. In recent years, it has been established that some of micro- and long-non-coding RNAs are differentially expressed; their roles and goals have been identified. As a consequence, it was shown that non-coding RNAs are excellent markers of a wide range of diseases. It is proposed that ncRNAs can be used as biomarkers in sports: in genetic testing of highly qualified athletes; in development of programs for the selection of young athletes; in identification of the genetic risk of injury and pathologies in athletes; in doping detection. Therefore, our studies focus on the identification of the localization and motifs of miRNAs and lncRNAs binding sites around and inside genes of endurance and speed-strength qualities (PPARD, NRF2, PGC-1, HIF-1, HIF-2, GYS1, HBA1, HBA2, HBB, ADRB2, NOS3, CHRM2, UCP2, UCP3, VEGF, EPO), genes of efficiency of muscle work (ACE, CK-MM, ACTN3, MLCK, AMPD1, IGF-1) and genes responsible for psychological characteristics (5HTT, BDNF, HTR2A (SR), DRD2, MTHFR).

Brief Bio: Ekaterina Derevyanchuk is a candidate of biological sciences, associate professor of the Genetics Department at the Academy of Biology and Biotechnology named after D.I. Ivanovsky, Southern Federal University, a member of the Vavilov Society of Geneticists and Breeders. Her work focuses on the study of the role of non-coding RNAs in the various diseases and the development of diagnostic test systems based on the data obtained. Particularly, her studies are related to the search of localization of ncRNAs binding sites around and inside genes associated with various diseases. Ekaterina Derevyanchuk is a winner of the All-Russian contest, held by the Foundation for Assistance to Small Innovative Enterprises (FASIE), the German Academic Exchange Service (DAAD) scholarship holder, winner of the young scientists contest held within the framework of the International Congress "Early Pregnancy” (RUDN, Moscow, Russia), co-owner of a small gold medal for the development of bioinformatics technology for searching for the relationship of organization scenarios in animal and human genomes of non-coding DNA and protein-coding DNA (RosBioTech, Moscow, Russia). She is author of the best poster presentation at the Interregional Scientific and Practical Conference "Cellular technologies for practical healthcare" (Yekaterinburg, Russia), and winner of the Competition for the best poster report in the framework of the International Conference of Young Scientists "New directions in Life Sciences" (Yerevan, Armenia).

Title: RNA dynamics and epitope changes from spaceflight and plans for Mars.

Abstract: The avalanche of easy-to-create genomics data has impacted almost all areas of medicine and science, from cancer patients and microbial diagnostics to molecular monitoring for astronauts in space. In this seminar, new discoveries from RNA- and DNA-sequencing across dozens of cities on Earth will be detailed, including the analysis of wastewater as a means to track SARS-CoV-2 levels, and also explore the investigation of new species found on the International Space Station. Recent technologies and algorithms from our laboratory and others demonstrate that an integrative, cross-kingdom view of patients (precision metagenomics) holds unprecedented biomedical potential to discern risk, improve diagnostic accuracy, and to map both genetic and epigenetic states around the world and in real-time. Finally, these methods and molecular tools work together to guide comprehensive, longitudinal, multi-omic views of human astronaut physiology and new RNA biology in the NASA Twins Study and several other missions, which lay the foundation for future long-duration spaceflight, including sequencing, quantifying, and engineering genomes to survive on other planets over the next 500 years (https://mitpress.mit.edu/books/next-500-years).

Brief Bio: Dr. Christopher Mason is a Professor of Genomics, Physiology, and Biophysics at Weill Cornell Medicine. He completed a dual B.S. in Genetics & Biochemistry at University of Wisconsin-Madison (2001), a PhD. in Genetics from Yale University (2006), Post-doctoral Fellowship in Clinical Genetics at Yale Medical School (2009) while also serving as the first Visiting Fellow of Genomics, Ethics, and Law at the Information Society Project at Yale Law School (2006-2009). In 2010, he became an Assistant Professor of Genomics, Physiology, and Biophysics at Weill Cornell Medicine, then promoted to Associate Professor in 2015, made the Director of the WorldQuant Initiative for Quantitative Prediction in 2017, and promoted to Full Professor in 2021. He also holds appointments at Tri-Institutional Program on Computational Biology and Medicine (Cornell, Memorial Sloan-Kettering Cancer Center and Rockefeller University), the Sandra and Edward Meyer Cancer Center, the Feil Family Brain and Mind Research Institute, (BMRI), and is an affiliate fellow of the Information Society Project (ISP) at Yale Law School, affiliate faculty of the Consortium for Space Genetics at Harvard Medical School, and a Core Faculty Member of New York Genome Center (NYGC). He was named as one of the “Brilliant Ten” Scientists by Popular Science, featured as a TEDMED speaker, and called “The Genius of Genetics” by 92Y. He has >250 peer-reviewed papers and scholarly works that have been featured on the covers of Nature, Science, Cell, Nature Biotechnology, Nature Microbiology, and Neuron, as well as legal briefs cited by the U.S. District Court and U.S. Supreme Court. He is an inventor on four patents, co-founder of five biotechnology start-up companies, and serves as an advisor to 17 others as well as 3 non-profits.

Title: From Organism-specific DNA Motifs to a Colon-Cancer-Survival Biomarker and Beyond

Abstract: In this presentation, I will review our analytical and experimental work on the "pyknons," a class of variable-length DNA motifs. We embarked on this journey sixteen years ago with a simple question: are there any statistically significant motifs comprising contiguous nucleotides that abound in intergenic or intronic regions of the genome and are also found in the span of messenger RNAs (mRNAs)? If they existed, such motifs would suggest logical links between the protein-coding part (~2%) and the non-protein-coding part (98%) of the genome. Moreover, the sense-sense and sense-antisense instances of any such motifs would be compelling candidates through which to implement long-distance regulatory control of mRNAs. A year later, we reported on a new class of DNA motifs and labeled them pyknons, from the Greek work for "dense." By definition, the discovered motifs suggest many-to-many logical connections between intergenic and intronic regions of the genome on one hand, and exons in nearly every known mRNA on the other. Our analyses of the human and mouse genomes also showed that the sequences of pyknons are organism-specific. Despite the lack of sequence conservation and synteny, we showed that the intronic instances of pyknons in human and mouse capture functional conservation.

Given these intriguing properties, we pursued the experimental characterization of several hundred pyknons. We found that human genome regions containing pyknons undergo marshaled transcription that is tissue-dependent and differs between normal and diseased tissue. One pyknon-containing region attracted our attention early on because it was differentially abundant between normal colon and colon cancer. We found that this particular pyknon is contained in a long non-coding RNA that we dubbed N-BLR. N-BLR is differentially abundant between normal colon and colon cancer, and its pyknon copy modulates the epithelial-to-mesenchymal transition affecting the overall survival of colon cancer patients. We found many more pyknon-containing long non-coding RNAs to be differentially abundant in colon and other cancers compared to normal tissue. Outside cancer, we found links between pyknons and early embryogenesis. Specifically, we showed that the genes that are up-regulated between the zygote and the blastocyst contain numerous pyknons whose sequences differ from those of the pyknons contained in the genes that are down-regulated.

We believe that these motifs are a feature of genome architecture used to implement wide-ranging, long-distance regulatory control of transcripts, among possibly other things. Computational analyses identified the motifs in the first place. Genome annotations helped shed a first light on what they might be doing. Targeted experimentation helped identify the biological context in which some pyknons are relevant and elucidated the functional role of one of them. More than three hundred thousand pyknon motifs are currently known for human and mouse combined. Except for a handful, most of these motifs remain uncharacterized and represent an untapped opportunity for more discoveries.

Brief Bio: Dr. Rigoutsos is a Professor in Thomas Jefferson University's Department of Pathology and the inaugural holder of the University’s Richard W. Hevner Chair in Computational Medicine. He also has joint appointments in the Department of Cancer Biology, and the Department of Biochemistry & Molecular Biology. In 2020, he was elected Fellow of the American Association for the Advancement of Science (AAAS). The Rigoutsos lab studies post-transcriptional regulation by short non-coding RNAs with an emphasis on three RNA classes: the microRNA isoforms (isomiRs), the tRNA-derived fragments (tRFs) and the rRNA-derived fragments (rRFs). Recently, the lab was the first to show in human tissues that the abundances of isomiRs, tRFs and rRFs depend on an individual’s sex, ethnicity, and age, as well as tissue, tissue state, and disease. Because isomiRs, tRFs, and rRFs regulate protein abundance, these findings have important implications for Precision Medicine and understanding the molecular biology of health disparities. The lab has already reported specific and sensitive biomarkers for 32 cancer types and several neurological disorders that are based on these RNA classes. In addition to helping build potent diagnostic and prognostic biomarkers, isomiRs, tRFs, and rRFs can also serve as promising candidate therapeutics.

Title: LncRNAs at the intersection of cancer pathways

Abstract: The roles of long noncoding RNAs (lncRNAs) in the regulation of gene expression in cancer networks remain incompletely understood. We have recently annotated de novo and characterized lncRNAs downstream of the p53 tumor suppressor, which orchestrates the transcriptional response to cellular stress. Our studies revealed a set of cis regulatory lncRNAs, which influence cancer pathways and processes through the modulation of their neighboring genes. We have further characterized the role of the lncRNA lincRNA-p21 in the transcriptional activation of its neighbor, the G1/S checkpoint factor Cdkn1a/p21, as well as the contribution of the lncRNA isoform Pvt1b to the transcriptional repression of its neighbor, the Myc oncogene. We show that production of the Pvt1b RNA downstream of p53 during the cellular response to stress is both necessary and sufficient to suppress Myc transcription in cis without altering the chromatin organization of the locus. Genetic inhibition of Pvt1b increases Myc levels and transcriptional activity and promotes cellular proliferation. Furthermore, Pvt1b loss dramatically accelerates tumor growth, but not tumor progression, in an autochthonous mutant K-ras-driven mouse model of lung cancer. These findings demonstrate that Pvt1b acts at the intersection of the p53 and Myc transcriptional networks to reinforce the anti-proliferative activities of p53.

Brief Bio: Nadya Dimitrova is an assistant professor in the Departments of Molecular, Cellular and Developmental Biology and Genetics at Yale University and a member of the Yale Center for RNA Science and Medicine and the Yale Cancer Center. She has a long-standing interest in understanding the functions and mechanisms of action of long noncoding RNAs (lncRNAs) in the context of cancer. Her work is focused on developing genetic models to study the roles of lncRNAs in normal and disease states and gaining deeper insights into mechanisms of lncRNAs. Nadya Dimitrova is the recipient of the HHMI Predoctoral Fellowship, the Damon Runyon Postdoctoral Fellowship Award, the Lung Cancer Research Foundation Scientific Merit Award, the Pew-Stewart Award for Cancer Research, the V Scholar Award, and the NCI Merit Award.

Title: Secondary Structure Global Alignment and Clustering for Improving Functional Classification and ncRNA Motif Discovery

Abstract: RNA secondary structure is more conserved than primary sequence and often key to noncoding RNA (ncRNA) function. Secondary structure prediction and analysis remains valuable because it is faster to compute than tertiary, and is more amenable for use in function prediction and classification. We created the bpRNA-1m RNA secondary structure meta-database, which contains more than 100,000 single-molecule (1m) RNA secondary structures that are richly annotated with the bpRNA structural annotation tool. This meta-database contains structures characterized through X-ray crystallography, nuclear magnetic resonance, electron microscopy, fluorescence transfer, and comparative sequence analysis, originating from 7 different source databases, and has been used by many labs to train machine learning models that predict secondary structure. The improvement of this database presents two key challenges. The first challenge is to identify erroneous structures that arose from comparative sequence methods and the projection of consensus structures to genomes where a structure is not well conserved or contains deletions. There is a need to systematically remove these spurious structures to refine bpRNA-1m into a more confident secondary structure database for machine learning and structural analyses. A second challenge is to combine structures from the different source databases in a systematic way, recognizing that they all use different nomenclature. Recognizing common structures has other applications in the discovery of novel RNA structural motifs. In this work, we present a novel secondary structure alignment and clustering method, bpRNA-align. bpRNA-align is built upon the bpRNA "structure array" sequence, which assigns a single-character structural feature code to each nucleotide in the RNA, producing flexible structure representations that depict the length of each structural feature with a small alphabet. bpRNA-align is a customized global structural alignment method, utilizing an inverted (gap extend costs more than gap open), context-specific affine gap penalty and a structural feature substitution matrix to compute similarity scores. Affinity-propagation clustering based on these similarity scores more accurately groups RNAs into appropriate family categories than other methods. The generation of a new database, bpRNA-1m-refined, without spurious structures and with a unified RNA nomenclature system will provide a more stable foundation for future machine learning and other investigations into RNA secondary structure. (This work is done in collaboration with Brittany Lasher, Oregon State University, Corvallis, Oregon, USA)

Brief Bio: David Hendrix is an associate professor at Oregon State in both the Department of Biochemistry and Biophysics (BB), and the Schol of Electrical Engineering and Computer Science (EECS). His work is in computational biology and bioinformatics, with work on systems biology, machine learning, and data science applied to a wide range of domains, including RNA structure and sequence analysis and genomics.

Title: Characterizing the Molecular Function of the Radiosensitizer Long Non-coding RNAs linc-SPRY3 in Male Lung Cancers.

Abstract: Ionizing radiation therapy (RT) is one of the most common treatment modalities for human cancers. Unfortunately, more than 40% of large tumors fail RT. For this reason, it is essential to identify the molecular pathways involved in the process of radiation susceptibility. Our preliminary data (published in the journal Cancer Research, 2020) indicates a group of lncRNAs expressed from the Y chromosome, known as linc-SPRY3 RNAs, are involved in ionizing radiation susceptibility in male non-small cell lung cancer (NSCLC) cells. The linc-SPRY3 family exhibit dose-dependent expression after RT in radiosensitive NSCLC cell lines but not in radioresistant NSCLC cell lines. Cytogenetic analysis revealed loss of chromosome Y (LOY) in the radioresistant NSCLC cell lines and loss and gain of function experiments demonstrated radiation sensitivity in male NSCLC cells involves linc-SPRY3 RNAs. Our recent preliminary data show that decreases in linc-SPRY3 RNAs expression increase AURKB, CDC6, and CDC25A expression through chromatin accessibility, and increased expression of these lncRNAs can reduce HMGA2 and c-Myc mRNAs stability by competitively binding to the RNA binding protein IGF2BP3. We also found that the transcription factors Oct-1 and c-Jun and hypoxia in the tumor microenvironment (TME), are involved in the regulation of linc-SPRY3 RNAs. The central hypothesis is that the linc-SPRY3 RNAs repress the expression of genes involved in radiation resistance such as AURKB, CDC6, and CDC25A through chromatin modifications and the oncogenes HMGA2 and c-Myc through RNA stability. We also hypothesize that the expression of these lncRNAs is regulated by a TME pathway that includes HIF1A/SP1/Oct-1 and c-Jun.

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.