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SOX4-Mediated Repression of Specific Trnas Inhibits Proliferation of Human Glioblastoma Cells

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SOX4-Mediated Repression of Specific Trnas Inhibits Proliferation of Human Glioblastoma Cells SOX4-mediated repression of specific tRNAs inhibits proliferation of human glioblastoma cells Jianjing Yanga,b,c, Derek K. Smithc,d, Haoqi Nia,b,c,KeWua,b, Dongdong Huanga,b, Sishi Pana,b,c, Adwait A. Sathee, Yu Tangc,d, Meng-Lu Liuc,d, Chao Xinge,f,g, Chun-Li Zhangc,d,1, and Qichuan Zhugea,b,1 aDepartment of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 325000; bZhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 325000; cDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; dHamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; eMcDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390; fDepartment of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390; and gDepartment of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390 Edited by S. Altman, Yale University, New Haven, CT, and approved February 5, 2020 (received for review November 15, 2019) Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) indicates that tRNA expression may also be under cell state- and essential for mRNA translation and ultimately cell growth and dependent regulations (12–16). proliferation. Whether and how individual tRNA genes are specif- In this study, we performed a systematic analysis on how ically regulated is not clear. Here, we report that SOX4, a well- NGN2/SOX4-mediated cell-fate reprogramming leads to cell known Pol II-dependent transcription factor that is critical for neuro- cycle exit of human glioblastoma cells. We found that SOX4, but genesis and reprogramming of somatic cells, also directly controls, not NGN2, quickly inhibits proliferation of these tumor cells. unexpectedly, the expression of a subset of tRNA genes and there- Unexpectedly, our chromatin immunoprecipitation sequencing fore protein synthesis and proliferation of human glioblastoma cells. (ChIP-seq) analysis revealed that a large fraction of SOX4 tar- Genome-wide location analysis through chromatin immunoprecipitation- gets are tRNA genes. Binding of SOX4 to these genes down- sequencing uncovers specific targeting of SOX4 to a subset of tRNA regulates their expression by blocking recruitment of TATA box tRNAiMet genes, including those for . Mechanistically, sequence- binding protein (TBP) and Pol III. Most importantly, knocking Met specific SOX4-binding impedes the recruitment of TATA box bind- down one of the SOX4 targets, tRNAi , could mimic the in- ing protein and Pol III to tRNA genes and thereby represses their Met hibitory effect of SOX4 on human glioblastoma cells. Such an expression. CRISPR/Cas9-mediated down-regulation of tRNAi inhibitory effect of SOX4 could be partially rescued by the ectopic greatly inhibits growth and proliferation of human glioblastoma Met Met tRNAi cells. Conversely, ectopic tRNAi partially rescues SOX4-mediated expression of a SOX4-irresponsive . These results pro- repression of cell proliferation. Together, these results uncover a vide insights into how expression of certain tRNA genes can be regulatory mode of individual tRNA genes to control cell behav- specifically regulated and how such regulation plays a critical bio- ior. Such regulation may coordinate codon usage and translation logical role, including proliferation of human glioblastoma cells. efficiency to meet the demands of diverse tissues and cell types, Results including cancer cells. SOX4 Inhibits Proliferation of Human Glioblastoma Cells. Neuronal tRNAiMet | tRNA expression | SOX4 | glioblastoma | mRNA translation reprogramming of human glioblastoma cells is accompanied by uman glioblastoma represents the most aggressive and deadly Significance Htype of brain tumor, characterized by uncontrolled growth and proliferation. Recently, we and others have shown that glio- Transfer RNAs (tRNAs) are essential for mRNA translation and blastoma cells can be reprogrammed into terminally differentiated protein synthesis. Their expression is tightly associated with neuron-like cells through ectopic expression of fate-determining cell states and is broadly controlled by the recruitment of Pol III factors (1–3). These include NGN2 (also known as NEUROG2) through intragenic elements. Whether and how tRNA genes in combination with SOX4 or SOX11 (1, 2). NGN2 is a basic could also be individually regulated is not known. In this study, helix–loop–helix transcription factor that specifies neuronal fate our results reveal that a polymerase II-dependent DNA-binding during development (4). SOX4 and SOX11 belong to the Sry- transcription factor can also regulate the expression of specific related high mobility group (HMG) box (SOX) family and both tRNAs through direct binding to DNA elements surrounding the are essential for development and neurogenesis (5, 6). NGN2 tRNA genes. Such a regulatory mode may have broader impli- serves as a pioneer factor to induce a neurogenic programs but cations into understanding how cells coordinate mRNA trans- itself is not sufficient for robust cell-fate reprogramming (1, 2). On lation and codon usage with cell state and behavior, such as the other hand, SOX4 promotes chromatin remodeling and dra- proliferation and reprogramming of human glioblastoma cells. matically enhances reprogramming of both human fibroblasts and glioblastoma cells (1). Cell cycle exit is a key feature of this Author contributions: J.Y., D.K.S., and C.-L.Z. designed research; J.Y., D.K.S., H.N., K.W., D.H., and S.P. performed research; Q.Z. supervised personnel and research; Y.T. and reprogramming process, but it is not clear how it is regulated. M.-L.L. contributed new reagents/analytic tools; J.Y., D.K.S., H.N., A.A.S., C.X., C.-L.Z., and Q.Z. Transfer RNAs (tRNAs) are essential for mRNA translation analyzed data; and J.Y. and C.-L.Z. wrote the paper. and protein synthesis (7–9). They perform housekeeping functions The authors declare no competing interest. for all cell types under physiological and pathological conditions. This article is a PNAS Direct Submission. Their expression is dependent on TFIIIC, TFIIIB, and RNA po- Published under the PNAS license. lymerase III (Pol III). Transcription of tRNA genes is initiated by Data deposition: The data reported in this paper have been deposited in the Gene Expression binding of TFIIIC to two intragenic control sequence blocks, the Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE138328). A and B boxes. TFIIIC then guides and positions TFIIIB to the 1To whom correspondence may be addressed. Email: Chun-Li.Zhang@UTSouthwestern. upstream-of-transcription start site. TFIIIB finally recruits Pol III edu or [email protected]. to start tRNA transcription. Approximately 500 tRNA genes This article contains supporting information online at https://www.pnas.org/lookup/suppl/ are dispersed throughout the human genome (10, 11). Although doi:10.1073/pnas.1920200117/-/DCSupplemental. they generally serve as housekeeping genes, emerging evidence First published March 2, 2020. 5782–5790 | PNAS | March 17, 2020 | vol. 117 | no. 11 www.pnas.org/cgi/doi/10.1073/pnas.1920200117 Downloaded by guest on September 25, 2021 cell cycle exit (1, 2). We examined individual contribution of the In addition to U251 glioblastoma cells, we also examined reprogramming factors to this process. Consistent with previous primary glioblastoma stem cells (GSCs) directly isolated from findings, ectopic expression of NGN2 and SOX4 progressively human brains with glioblastoma. These GSCs were sorted based but nearly completely reprogrammed U251 glioblastoma cells into on expression of CD133, a marker enriched in tumor stem cells, neuronal morphology by 12 d postviral infection (dpi), whereas and were maintained as self-renewable neurospheres in culture. neither NGN2 nor SOX4 alone had such an effect (Fig. 1A). When orthotopically transplanted, each of these GSC isolates When cell proliferation was analyzed by expression of Ki67, an could give rise to infiltrative and malignant brain tumors in nude endogenous marker for all active cell cycles, coexpression of mice (17). GSC proliferation was directly examined by Ki67 SI Appendix NGN2 and SOX4 also gradually induced cell cycle exit during this staining and BrdU incorporation assays ( ,Fig.S1). 12-d time-course analysis (Fig. 1 A and B). Unexpectedly, SOX4 Expression of SOX4 remarkably decreased the number of GSCs but not NGN2 dramatically and rapidly enabled U251 cells to exit that stained positive for Ki67 and BrdU at all of the analyzed time SI Appendix A–D the cell cycle. Approximately 40% and 90% of SOX4-expressing points ( ,Fig.S1 ). Measuring total cellular ATP contents of viable cells also showed completely halted increases by cells stained negative for Ki67 at 3 and 12 dpi, respectively (Fig. SI Ap- 1B). This is in sharp contrast to NGN2-expressing cells, about 50% SOX4 expression in all three independent GSC isolates ( + pendix E of which were still Ki67 at 12 dpi. ,Fig.S1 ). These were in sharp contrast to the control GFP- Cell proliferation was further analyzed by incorporation of expressing GSCs, which in general doubled viable cells from 3 to 7 dpi. Together, the above results clearly indicate that SOX4 po- BrdU, a synthetic analog of thymidine that can only be
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