The Expression Profiles of lncRNAs and Their Regulatory Network During Smek1/2 Knockout Mouse Neural Stem Cells Differentiation

Author(s): Qichang Yang, Jing Wu, Jian Zhao, Tianyi Xu, Ping Han*, Xiaofeng Song*.

Journal Name: Current Bioinformatics

Volume 15 , Issue 1 , 2020

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Abstract:

Background: Previous studies indicated that the cell fate of neural stem cells (NSCs) after differentiation is determined by Smek1, one isoform of suppressor of Mek null (Smek). Smek deficiency prevents NSCs from differentiation, thus affects the development of nervous system. In recent years, lncRNAs have been found to participate in numerous developmental and biological pathways. However, the effects of knocking out Smek on the expression profiles of lncRNAs during the differentiation remain unknown.

Objective: This study is to explore the expression profiles of lncRNAs and their possible function during the differentiation from Smek1/2 knockout NSCs.

Methods: We obtained NSCs from the C57BL/6J mouse fetal cerebral cortex. One group of NSCs was from wildtype mouse (WT group), while another group was from knocked out Smek1/2 (KO group).

Results: By analyzing the RNA-Seq data, we found that after knocking out Smek1/2, the expression profiles of mRNAs and lncRNAs revealed significant changes. Analyses indicated that these affected mRNAs have connections with the pathway network for the differentiation and proliferation of NSCs. Furthermore, we performed a co-expression network analysis on the differentially expressed mRNAs and lncRNAs, which helped reveal the possible regulatory rules of lncRNAs during the differentiation after knocking out Smek1/2.

Conclusion: By comparing group WT with KO, we found 366 differentially expressed mRNAs and 12 lncRNAs. GO and KEGG enrichment analysis on these mRNAs suggested their relationships with differentiation and proliferation of NSCs. Some of these mRNAs and lncRNAs have been verified to play regulatory roles in nervous system. Analyses on the co-expression network also indicated the possible functions of affected mRNAs and lncRNAs during NSCs differentiation after knocking out Smek1/2.

Keywords: lncRNA, expression profile, Smek, neural stem cell, differentiation, KEGG.

[1]
Merkle FT, Alvarez-Buylla A. Neural stem cells in mammalian development. Curr Opin Cell Biol 2006; 18(6): 704-9.
[http://dx.doi.org/10.1016/j.ceb.2006.09.008] [PMID: 17046226]
[2]
Tourette C, Farina F, Vazquez-Manrique RP, et al. The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity. PLoS Biol 2014; 12(6) e1001895
[http://dx.doi.org/10.1371/journal.pbio.1001895] [PMID: 24960609]
[3]
Merkle FT, Alvarez-Buylla A. Neural stem cells in mammalian development. Curr Opin Cell Biol 2006; 18(6): 704-9.
[http://dx.doi.org/10.1016/j.ceb.2006.09.008] [PMID: 17046226]
[4]
Stevens HE, Smith KM, Rash BG, Vaccarino FM. Neural stem cell regulation, fibroblast growth factors, and the developmental origins of neuropsychiatric disorders. Front Neurosci 2010; 4: 59.
[http://dx.doi.org/10.3389/fnins.2010.00059] [PMID: 20877431]
[5]
Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci 2009; 32(9): 485-95.
[http://dx.doi.org/10.1016/j.tins.2009.05.007] [PMID: 19712980]
[6]
Thomas RM, Peterson DA. Even neural stem cells get the blues: evidence for a molecular link between modulation of adult neurogenesis and depression Gene Expr 2008; 14(3): 183-93.
[PMID: 18590054]
[7]
Johnson MA, Ables JL, Eisch AJ. Cell-intrinsic signals that regulate adult neurogenesis in vivo: insights from inducible approaches. BMB Rep 2009; 42(5): 245-59.
[http://dx.doi.org/10.5483/BMBRep.2009.42.5.245] [PMID: 19470237]
[8]
Lai K, Kaspar BK, Gage FH, Schaffer DV. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 2003; 6(1): 21-7.
[http://dx.doi.org/10.1038/nn983] [PMID: 12469128]
[9]
Moon BS, Kim HY, Kim MY, et al. Sur8/Shoc2 involves both inhibition of differentiation and maintenance of self-renewal of neural progenitor cells via modulation of extracellular signal-regulated kinase signaling. Stem Cells 2011; 29(2): 320-31.
[http://dx.doi.org/10.1002/stem.586] [PMID: 21732489]
[10]
Iranfar N, Fuller D, Loomis WF. Genome-wide expression analyses of gene regulation during early development of Dictyostelium discoideum. Eukaryot Cell 2003; 2(4): 664-70.
[http://dx.doi.org/10.1128/EC.2.4.664-670.2003] [PMID: 12912885]
[11]
Mendoza MC, Du F, Iranfar N, et al. Loss of SMEK, a novel, conserved protein, suppresses MEK1 null cell polarity, chemotaxis, and gene expression defects. Mol Cell Biol 2005; 25(17): 7839-53.
[http://dx.doi.org/10.1128/MCB.25.17.7839-7853.2005] [PMID: 16107728]
[12]
Chen GI, Tisayakorn S, Jorgensen C, D’Ambrosio LM, Goudreault M, Gingras AC. PP4R4/KIAA1622 forms a novel stable cytosolic complex with phosphoprotein phosphatase 4. J Biol Chem 2008; 283(43): 29273-84.
[http://dx.doi.org/10.1074/jbc.M803443200] [PMID: 18715871]
[13]
Mendoza MC, Booth EO, Shaulsky G, Firtel RA. MEK1 and protein phosphatase 4 coordinate Dictyostelium development and chemotaxis. Mol Cell Biol 2007; 27(10): 3817-27.
[http://dx.doi.org/10.1128/MCB.02194-06] [PMID: 17353263]
[14]
Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 2004; 5(9): 691-701.
[http://dx.doi.org/10.1038/nrg1427] [PMID: 15372092]
[15]
Wolff S, Ma H, Burch D, Maciel GA, Hunter T, Dillin A. SMK-1, an essential regulator of DAF-16-mediated longevity. Cell 2006; 124(5): 1039-53.
[http://dx.doi.org/10.1016/j.cell.2005.12.042] [PMID: 16530049]
[16]
Chowdhury D, Xu X, Zhong X, et al. A PP4-phosphatase complex dephosphorylates γ-H2AX generated during DNA replication. Mol Cell 2008; 31(1): 33-46.
[http://dx.doi.org/10.1016/j.molcel.2008.05.016] [PMID: 18614045]
[17]
Yoon YS, Lee MW, Ryu D, et al. Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis. Proc Natl Acad Sci USA 2010; 107(41): 17704-9.
[http://dx.doi.org/10.1073/pnas.1012665107] [PMID: 20876121]
[18]
Bielen H, Houart C. The Wnt cries many: Wnt regulation of neurogenesis through tissue patterning, proliferation, and asymmetric cell division. Dev Neurobiol 2014; 74(8): 772-80.
[http://dx.doi.org/10.1002/dneu.22168] [PMID: 24488703 ]
[19]
Lyu J, Jho EH, Lu W. Smek promotes histone deacetylation to suppress transcription of Wnt target gene brachyury in pluripotent embryonic stem cells. Cell Res 2011; 21(6): 911-21.
[http://dx.doi.org/10.1038/cr.2011.47] [PMID: 21423269]
[20]
Huang J, Xue L. Loss offlfl triggers JNK-dependent cell death in drosophila. BioMed Res Int 2015; 2015(16)623573
[http://dx.doi.org/10.1155/2015/623573] [PMID: 26583122]
[21]
Yang R, Ren M, Rui Q, Wang D. A mir-231-Regulated protection mechanism against the toxicity of graphene oxide in nematode caenorhabditis elegans. Sci Rep 2016; 6: 32214.
[http://dx.doi.org/10.1038/srep32214] [PMID: 27558892]
[22]
Liang S, Xu S, Zhang D, He J, Chu M. Reproductive toxicity of nanoscale graphene oxide in male mice. Nanotoxicology 2015; 9(1): 92-105.
[http://dx.doi.org/10.3109/17435390.2014.893380] [PMID: 24621344]
[23]
Zhao Y, Wu Q, Wang D. A microRNAs-mRNAs network involved in the control of graphene oxide toxicity in Caenorhabditis elegans. RSC Advances 2015; 5(112): 92394-405.
[http://dx.doi.org/10.1039/C5RA16142H]
[24]
Lyu J, Kim HR, Yamamoto V, et al. Protein phosphatase 4 and Smek complex negatively regulate Par3 and promote neuronal differentiation of neural stem/progenitor cells. Cell Rep 2013; 5(3): 593-600.
[http://dx.doi.org/10.1016/j.celrep.2013.09.034] [PMID: 24209749]
[25]
Chang WH, Choi SH, Moon BS, et al. Smek1/2 is a nuclear chaperone and cofactor for cleaved Wnt receptor Ryk, regulating cortical neurogenesis. Proc Natl Acad Sci USA 2017; 114(50): E10717-25.
[http://dx.doi.org/10.1073/pnas.1715772114] [PMID: 29180410]
[26]
Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem 2012; 81(1): 145-66.
[http://dx.doi.org/10.1146/annurev-biochem-051410-092902] [PMID: 22663078]
[27]
Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell 2013; 152(6): 1298-307.
[http://dx.doi.org/10.1016/j.cell.2013.02.012] [PMID: 23498938]
[28]
Ramos AD, Attenello FJ, Lim DA. Uncovering the roles of long noncoding RNAs in neural development and glioma progression. Neurosci Lett 2016; 625: 70-9.
[http://dx.doi.org/10.1016/j.neulet.2015.12.025] [PMID: 26733304]
[29]
Derrien T, Guigo R. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 2012; 22(9): 1775-89.
[30]
Ramos AD, Diaz A, Nellore A, et al. Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo. Cell Stem Cell 2013; 12(5): 616-28.
[http://dx.doi.org/10.1016/j.stem.2013.03.003] [PMID: 23583100]
[31]
Johnson R, Stanton LW. Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J 2014; 31(3): 522-33.
[32]
Sousa-Nunes R, Chia W, Somers WG. Protein phosphatase 4 mediates localization of the Miranda complex during Drosophila neuroblast asymmetric divisions. Genes Dev 2009; 23(3): 359-72.
[http://dx.doi.org/10.1101/gad.1723609] [PMID: 19204120]
[33]
Knock E, Pereira J, Lombard PD, et al. The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex. Neural Dev 2015; 10(1): 13.
[http://dx.doi.org/10.1186/s13064-015-0040-z] [PMID: 25934499]
[34]
Gould VC, Okazaki A, Avison MB. Coordinate hyperproduction of SmeZ and SmeJK efflux pumps extends drug resistance in Stenotrophomonas maltophilia. Antimicrob Agents Chemother 2013; 57(1): 655-7.
[http://dx.doi.org/10.1128/AAC.01020-12] [PMID: 23147729]
[35]
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116(2): 281-97.
[http://dx.doi.org/10.1016/S0092-8674(04)00045-5] [PMID: 14744438]
[36]
Zhong J, Kim HT, Lyu J, Yoshikawa K, Nakafuku M, Lu W. The Wnt receptor Ryk controls specification of GABAergic neurons versus oligodendrocytes during telencephalon development. Development 2011; 138(3): 409-19.
[http://dx.doi.org/10.1242/dev.061051] [PMID: 21205786]
[37]
Wei Z, Yang Y, Zhang P, et al. Klf4 interacts directly with Oct4 and Sox2 to promote reprogramming. Stem Cells 2009; 27(12): 2969-78.
[http://dx.doi.org/10.1002/stem.231] [PMID: 19816951]
[38]
Dai X, Iwasaki H, Watanabe M, Okabe S. Dlx1 transcription factor regulates dendritic growth and postsynaptic differentiation through inhibition of neuropilin-2 and PAK3 expression. Eur J Neurosci 2014; 39(4): 531-47.
[http://dx.doi.org/10.1111/ejn.12413] [PMID: 24236816]
[39]
de Melo J, Du G, Fonseca M, et al. Dlx1 and Dlx2 function is necessary for terminal differentiation and survival of late-born retinal ganglion cells in the developing mouse retina. Development 2005; 132(2): 311-22.
[http://dx.doi.org/10.1242/dev.01560] [PMID: 15604100]
[40]
Wu Q, Zhou X, Han X, et al. Genome-wide identification and functional analysis of long noncoding RNAs involved in the response to graphene oxide. Biomaterials 2016; 102: 277-91.
[http://dx.doi.org/10.1016/j.biomaterials.2016.06.041] [PMID: 27348851]
[41]
Moon BS, Yun HM, Chang WH, et al. Smek promotes cortico-genesis through regulating Mbd3's stability and Mbd3/NuRD complex recruitment to genes associated with neurogenesis. PLoS Biol 2017; 15(5) e2001220
[http://dx.doi.org/10.1371/journal.pbio.2001220] [PMID: 28467410]
[42]
Potter GB, Petryniak MA, Shevchenko E, McKinsey GL, Ekker M, Rubenstein JL. Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons. Mol Cell Neurosci 2009; 40(2): 167-86.
[http://dx.doi.org/10.1016/j.mcn.2008.10.003] [PMID: 19026749]
[43]
de Melo J, Qiu X, Du G, Cristante L, Eisenstat DD. Dlx1, Dlx2, Pax6, Brn3b, and Chx10 homeobox gene expression defines the retinal ganglion and inner nuclear layers of the developing and adult mouse retina. J Comp Neurol 2003; 461(2): 187-204.
[http://dx.doi.org/10.1002/cne.10674] [PMID: 12724837]
[44]
Wang B, Long JE, Flandin P, et al. Loss of Gsx1 and Gsx2 function rescues distinct phenotypes in Dlx1/2 mutants. J Comp Neurol 2013; 521(7): 1561-84.
[http://dx.doi.org/10.1002/cne.23242] [PMID: 23042297]
[45]
Silbereis JC, Nobuta H, Tsai HH, et al. Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 2014; 81(3): 574-87.
[http://dx.doi.org/10.1016/j.neuron.2013.11.024] [PMID: 24507192]
[46]
Zheng Y, Jia L. Long noncoding RNAs related to the odontogenic potential of dental mesenchymal cells in mice. Arch Oral Biol 2016; 67: 1-8.
[http://dx.doi.org/10.1016/j.archoralbio.2016.03.001] [PMID: 26986487]
[47]
Wu YJ, Xu MY, Wang L, Sun BL, Gu GX. Analysis of EphA5 receptor in the developing rat brain: an in vivo study in congenital hypothyroidism model. Eur J Pediatr 2013; 172(8): 1077-83.
[48]
Noh H, Park E, Park S. In vivo expression of ephrinA5-Fc in mice results in cephalic neural crest agenesis and craniofacial abnormalities. Mol Cells 2014; 37(1): 59-65.
[http://dx.doi.org/10.14348/molcells.2014.2279] [PMID: 24552711]
[49]
Cooper MA, Crockett DP, Nowakowski RS, Gale NW, Zhou R. Distribution of EphA5 receptor protein in the developing and adult mouse nervous system. J Comp Neurol 2009; 514(4): 310-28.
[http://dx.doi.org/10.1002/cne.22030] [PMID: 19326470 ]


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VOLUME: 15
ISSUE: 1
Year: 2020
Page: [77 - 88]
Pages: 12
DOI: 10.2174/1574893614666190308160507
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