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oai:www.ideals.illinois.edu:2142/108231 2023-07-11 col_2142_5131 col_2142_14855 com_2142_5130 com_2142_14854 com_2142_14793 com_2142_8903

Made available in DSpace on 2020-08-27T00:46:52Z (GMT). No. of bitstreams: 2 SUN-DISSERTATION-2020.pdf: 9175277 bytes, checksum: e2efccee2ecdb753df410d65867ed198 (MD5) LICENSE.txt: 4206 bytes, checksum: d9400be8634f345516a8365c493c941a (MD5) Previous issue date: 2020-03-17 Embargo set by: Seth Robbins for item 115844 Lift date: 2022-08-27T00:46:59Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 115844 Lift date: 2022-08-27T00:50:22Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 115844 Lift date: 2022-08-27T00:51:40Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Prasanth, Kannanganattu V Prasanth, Kannanganattu V Chen, Jie Ceman, Stephanie Kalsotra, Auinash Sun, Qinyu 2020-08-27T00:46:52Z 2020-08-27T00:46:52Z 2022-08-27T00:51:40Z 2020-03-17 2020-05 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. Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2022-05-01 The student, Qinyu Sun, accepted the attached license on 2020-03-12 at 20:35. The student, Qinyu Sun, submitted this Dissertation for approval on 2020-03-12 at 20:36. This Dissertation was approved for publication on 2020-03-17 at 08:31. DSpace SAF Submission Ingestion Package generated from Vireo submission #14895 on 2020-08-25 at 17:39:01 Author requested closed access (OA after 2yrs) in Vireo ETD system Limited application/pdf http://hdl.handle.net/2142/108231 en Copyright 2020 Qinyu Sun lncRNA, cell cycle, microRNA-host-gene Role of microRNA-host-lncRNAs in cell cycle text Thesis Cell & Developmental Biology Cell and Developmental Biology University of Illinois at Urbana-Champaign Dissertation Ph.D.