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Title:Role of microRNA-host-lncRNAs in cell cycle
Author(s):Sun, Qinyu
Director of Research:Prasanth, Kannanganattu V
Doctoral Committee Chair(s):Prasanth, Kannanganattu V
Doctoral Committee Member(s):Chen, Jie; Ceman, Stephanie; Kalsotra, Auinash
Department / Program:Cell & Developmental Biology
Discipline:Cell and Developmental Biology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):lncRNA, cell cycle, microRNA-host-gene
Abstract:Long non-coding RNAs (lncRNAs) regulate vital biological processes, including cell proliferation, differentiation and development. A subclass of lncRNAs is synthesized from microRNA (miRNA) host genes (MIRHGs) due to pre-miRNA processing and are categorized as microRNA-host gene lncRNAs (lnc-MIRHGs). Presently, the cellular function of most lnc-MIRHGs is not well understood. In this thesis, I describe studies showing the potential role of two lnc-MIRHGs in cell cycle progression. In chapter 2, I focus on investigating the role of lnc-MIRHGs in regulating the cell cycle re-entry post quiescence. Cellular quiescence is coupled with cellular development, tissue homeostasis, and cancer progression. Both quiescence and cell cycle re-entry are controlled by active and precise regulation of gene expression. However, the roles of long noncoding RNAs (lncRNAs) during these processes remain to be elucidated. By performing a genome-wide transcriptome analysis, I identify thousands of differentially expressed lncRNAs, including ~30 lnc-MIRHGs, during cellular quiescence and during serum-stimulation in human diploid fibroblast cells. I observe that the mature MIR222HG display serum-stimulated induction due to enhanced pre-RNA splicing. Serum-stimulated binding of the pre-mRNA splicing factor SRSF1 to a micro-exon, which partially overlaps with the primary miR-222 precursor, facilitates enhanced MIR222HG splicing. In serum-stimulated cells, SRSF1 negatively regulates the Drosha/DGCR8-catalyzed cleavage of pri-miR-222, thereby increasing the cellular pool of the mature MIR222HG. Further, loss-of-function studies indicate that the mature MIR222HG facilitates the serum-stimulated cell cycle re-entry in a microRNA-independent manner. Mechanistically, MIR222HG, along with ILF3/2 complex, forms a RNA:RNA duplex with DNM3OS lncRNA, thereby promoting DNM3OS stability. This study identifies a mechanism in which the interplay between splicing versus microprocessor complex dictates the serum-induced expression of MIR222HG for efficient cell cycle re-entry. In Chapter 3, I demonstrate a microRNA-independent role for a nuclear-enriched and G1-elevated lnc-MIRHG in cell cycle progression of human osteosarcoma. Our knowledge of protein-coding genes in cell cycle regulation is rather complete, but the roles of lncRNAs in this important biological process remain to be elucidated. By performing the genome-wide transcriptome profiling analysis, I discovered 38 phase-specific lnc-MIRHGs that showed elevated expression in one particular cell cycle stage (G1, G1S, S, G2, or M). I further show that MIR100HG produces spliced and stable lncRNAs that display elevated levels during the G1 phase of the cell cycle. Depletion of MIR100HG-encoded lncRNAs in human cells results in aberrant cell cycle progression without altering the levels of miRNA encoded within MIR100HG. Notably, MIR100HG interacts with HuR/ELAVL1 as well as with several HuR-target mRNAs. Further, MIR100HG-depleted cells show reduced interaction between HuR and three of its target mRNAs, indicating that MIR100HG facilitates interaction between HuR and target mRNAs. This study unearths novel roles played by a MIRHG-encoded lncRNA in regulating RNA binding protein activity. In Chapter 4, I summarize my findings during the discovery of lnc-MIRHGs and discuss my opinions about the future directions of lnc-MIRHGs research.
Issue Date:2020-03-17
Rights Information:Copyright 2020 Qinyu Sun
Date Available in IDEALS:2020-08-27
Date Deposited:2020-05

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