Alternative splicing switching in stem cell lineages

Abstract

The application of stem cells to regenerative medicine depends on a thorough understanding of the molecular mechanisms underlying their pluripotency. Many studies have identified key transcription factor-regulated transcriptional networks and chromatin landscapes of embryonic and a number of adult stem cells. In addition, recent publications have revealed another interesting molecular feature of stem cells— a distinct alternative splicing pattern. Thus, it is possible that both the identity and activity of stem cells are maintained by stem cell-specific mRNA isoforms, while switching to different isoforms ensures proper differentiation. In this review, we will discuss the generality of mRNA isoform switching and its interaction with other molecular mechanisms to regulate stem cell pluripotency, as well as the reprogramming process in which differentiated cells are induced to become pluripotent stem cell-like cells (iPSCs).

Keywords

alternative splicing / embryonic stem cells / adult stem cells / stem cell maintenance and differentiation / post-transcriptional regulation / epigenetic regulation

References

[1] Allemand E, Batsché E, Muchardt C (2008). Splicing, transcription, and chromatin: a ménage à trois. Curr Opin Genet Dev, 18(2): 145-151

[2] Alló M, Buggiano V, Fededa J P, Petrillo E, Schor I, de la Mata M, Agirre E, Plass M, Eyras E, Elela S A, Klinck R, Chabot B, Kornblihtt A R (2009). Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nat Struct Mol Biol, 16(7): 717-724

[3] Atlasi Y, Mowla S J, Ziaee S A, Gokhale P J, Andrews P W (2008). OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells, 26(12): 3068-3074

[4] Azuara V, Perry P, Sauer S, Spivakov M, Jørgensen H F, John R M, Gouti M, Casanova M, Warnes G, Merkenschlager M, Fisher A G (2006). Chromatin signatures of pluripotent cell lines. Nat Cell Biol, 8(5): 532-538

[5] Barash Y, Calarco J A, Gao W, Pan Q, Wang X, Shai O, Blencowe B J, Frey B J (2010). Deciphering the splicing code. Nature, 465(7294): 53-59

[6] Barski A, Cuddapah S, Cui K, Roh T Y, Schones D E, Wang Z, Wei G, Chepelev I, Zhao K (2007). High-resolution profiling of histone methylations in the human genome. Cell, 129(4): 823-837

[7] Bernstein B E, Mikkelsen T S, Xie X, Kamal M, Huebert D J, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber S L, Lander E S (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 125(2): 315-326

[8] Bland C S, Cooper T A (2007). Micromanaging alternative splicing during muscle differentiation. Dev Cell, 12(2): 171-172

[9] Bland C S, Wang E T, Vu A, David M P, Castle J C, Johnson J M, Burge C B, Cooper T A (2010). Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res, 38(21): 7651-7664

[10] Boutz P L, Chawla G, Stoilov P, Black D L (2007a). MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development. Genes Dev, 21(1): 71-84

[11] Boutz P L, Stoilov P, Li Q, Lin C H, Chawla G, Ostrow K, Shiue L, Ares M Jr, Black D L (2007b). A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev, 21(13): 1636-1652

[12] Boyer L A, Lee T I, Cole M F, Johnstone S E, Levine S S, Zucker J P, Guenther M G, Kumar R M, Murray H L, Jenner R G, Gifford D K, Melton D A, Jaenisch R, Young R A (2005). Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 122(6): 947-956

[13] Boyer L A, Mathur D, Jaenisch R (2006a). Molecular control of pluripotency. Curr Opin Genet Dev, 16(5): 455-462

[14] Boyer L A, Plath K, Zeitlinger J, Brambrink T, Medeiros L A, Lee T I, Levine S S, Wernig M, Tajonar A, Ray M K, Bell G W, Otte A P, Vidal M, Gifford D K, Young R A, Jaenisch R (2006b). Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature, 441(7091): 349-353

[15] Chawla G, Lin C H, Han A, Shiue L, Ares M Jr, Black D L (2009). Sam68 regulates a set of alternatively spliced exons during neurogenesis. Mol Cell Biol, 29(1): 201-213

[16] Chen X (2008). Stem cells: what can we learn from flies? Fly (Austin), 2(1): 19-28

[17] Cover T M, Thomas J A (1991). Elements of information theory, 1st Edition. New York: Wiley-Interscience

[18] Das S,Jena S,Levasseur D N (2011). Alternative splicing produces nanog protein variants with different capacities for self-renewal and pluripotency in embryonic stem cells. J Biol Chem, 286(49):42690-42703

[19] Eun S H, Gan Q, Chen X (2010). Epigenetic regulation of germ cell differentiation. Curr Opin Cell Biol, 22(6): 737-743

[20] Evans M J, Kaufman M H (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819): 154-156

[21] Fuller M T, Spradling A C (2007). Male and female Drosophila germline stem cells: two versions of immortality. Science, 316(5823): 402-404

[22] Gabut M, Samavarchi-Tehrani P, Wang X, Slobodeniuc V, O’Hanlon D, Sung H K, Alvarez M, Talukder S, Pan Q, Mazzoni E O, Nedelec S, Wichterle H, Woltjen K, Hughes T R, Zandstra P W, Nagy A, Wrana J L, Blencowe B J (2011). An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming. Cell, 147(1): 132-146

[23] Gan Q, Chepelev I, Wei G, Tarayrah L, Cui K, Zhao K, Chen X (2010). Dynamic regulation of alternative splicing and chromatin structure in Drosophila gonads revealed by RNA-seq. Cell Res, 20(7): 763-783

[24] Gaspar-Maia A, Alajem A, Polesso F, Sridharan R, Mason M J, Heidersbach A, Ramalho-Santos J, McManus M T, Plath K, Meshorer E, Ramalho-Santos M (2009). Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature, 460(7257): 863-868

[25] Guan K, Nayernia K, Maier L S, Wagner S, Dressel R, Lee J H, Nolte J, Wolf F, Li M, Engel W, Hasenfuss G (2006). Pluripotency of spermatogonial stem cells from adult mouse testis. Nature, 440(7088): 1199-1203

[26] Guenther M G, Levine S S, Boyer L A, Jaenisch R, Young R A (2007). A chromatin landmark and transcription initiation at most promoters in human cells. Cell, 130(1): 77-88

[27] Jurica M S, Moore M J (2003). Pre-mRNA splicing: awash in a sea of proteins. Mol Cell, 12(1): 5-14

[28] Kanatsu-Shinohara M, Inoue K, Lee J, Yoshimoto M, Ogonuki N, Miki H, Baba S, Kato T, Kazuki Y, Toyokuni S, Toyoshima M, Niwa O, Oshimura M, Heike T, Nakahata T, Ishino F, Ogura A, Shinohara T (2004). Generation of pluripotent stem cells from neonatal mouse testis. Cell, 119(7): 1001-1012

[29] Kim J, Chu J, Shen X, Wang J, Orkin S H (2008). An extended transcriptional network for pluripotency of embryonic stem cells. Cell, 132(6): 1049-1061

[30] Kunarso G, Wong K Y, Stanton L W, Lipovich L (2008). Detailed characterization of the mouse embryonic stem cell transcriptome reveals novel genes and intergenic splicing associated with pluripotency. BMC Genomics, 9(1): 155

[31] Lareau L F, Inada M, Green R E, Wengrod J C, Brenner S E (2007). Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature, 446(7138): 926-929

[32] Lee J, Kim H K, Rho J Y, Han Y M, Kim J (2006a). The human OCT-4 isoforms differ in their ability to confer self-renewal. J Biol Chem, 281(44): 33554-33565

[33] Lee T I, Jenner R G, Boyer L A, Guenther M G, Levine S S, Kumar R M, Chevalier B, Johnstone S E, Cole M F, Isono K, Koseki H, Fuchikami T, Abe K, Murray H L, Zucker J P, Yuan B, Bell G W, Herbolsheimer E, Hannett N M, Sun K, Odom D T, Otte A P, Volkert T L, Bartel D P, Melton D A, Gifford D K, Jaenisch R, Young R A (2006b). Control of developmental regulators by Polycomb in human embryonic stem cells. Cell, 125(2): 301-313

[34] Lemischka I R, Pritsker M (2006). Alternative splicing increases complexity of stem cell transcriptome. Cell Cycle, 5(4): 347-351

[35] Loh Y H, Wu Q, Chew J L, Vega V B, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong K Y, Sung K W, Lee C W, Zhao X D, Chiu K P, Lipovich L, Kuznetsov V A, Robson P, Stanton L W, Wei C L, Ruan Y, Lim B, Ng H H (2006). The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet, 38(4): 431-440

[36] Losick V P, Morris L X, Fox D T, Spradling A (2011). Drosophila stem cell niches: a decade of discovery suggests a unified view of stem cell regulation. Dev Cell, 21(1): 159-171

[37] Luco R F, Allo M, Schor I E, Kornblihtt A R, Misteli T (2011). Epigenetics in alternative pre-mRNA splicing. Cell, 144(1): 16-26

[38] Luco R F, Misteli T (2011). More than a splicing code: integrating the role of RNA, chromatin and non-coding RNA in alternative splicing regulation. Curr Opin Genet Dev, 21(4): 366-372

[39] Luco R F, Pan Q, Tominaga K, Blencowe B J, Pereira-Smith O M, Misteli T (2010). Regulation of alternative splicing by histone modifications. Science, 327(5968): 996-1000

[40] Martin G R (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA, 78(12): 7634-7638

[41] Mayshar Y, Rom E, Chumakov I, Kronman A, Yayon A, Benvenisty N (2008). Fibroblast growth factor 4 and its novel splice isoform have opposing effects on the maintenance of human embryonic stem cell self-renewal. Stem Cells, 26(3): 767-774

[42] Mikkelsen T S, Ku M, Jaffe D B, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim T K, Koche R P, Lee W, Mendenhall E, O’Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander E S, Bernstein B E (2007). Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature, 448(7153): 553-560

[43] Molnár A, Georgopoulos K (1994). The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol, 14(12): 8292-8303

[44] Morrison S J, Kimble J (2006). Asymmetric and symmetric stem-cell divisions in development and cancer. Nature, 441(7097): 1068-1074

[45] Morrison S J, Spradling A C (2008). Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell, 132(4): 598-611

[46] Muñoz M J, Pérez Santangelo M S, Paronetto M P, de la Mata M, Pelisch F, Boireau S, Glover-Cutter K, Ben-Dov C, Blaustein M, Lozano J J, Bird G, Bentley D, Bertrand E, Kornblihtt A R (2009). DNA damage regulates alternative splicing through inhibition of RNA polymerase II elongation. Cell, 137(4): 708-720

[47] Nelles D A, Yeo G W (2010). Alternative splicing in stem cell self-renewal and diferentiation. Adv Exp Med Biol, 695: 92-104

[48] Ni J Z, Grate L, Donohue J P, Preston C, Nobida N, O’Brien G, Shiue L, Clark T A, Blume J E, Ares M Jr (2007). Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev, 21(6): 708-718

[49] Park I H, Zhao R, West J A, Yabuuchi A, Huo H, Ince T A, Lerou P H, Lensch M W, Daley G Q (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature, 451(7175): 141-146

[50] Pritsker M, Doniger T T, Kramer L C, Westcot S E, Lemischka I R (2005). Diversification of stem cell molecular repertoire by alternative splicing. Proc Natl Acad Sci USA, 102(40): 14290-14295

[51] Rao S, Zhen S, Roumiantsev S, McDonald L T, Yuan G C, Orkin S H (2010). Differential roles of Sall4 isoforms in embryonic stem cell pluripotency. Mol Cell Biol, 30(22): 5364-5380

[52] Richard S, Torabi N, Franco G V, Tremblay G A, Chen T, Vogel G, Morel M, Cléroux P, Forget-Richard A, Komarova S, Tremblay M L, Li W, Li A, Gao Y J, Henderson J E (2005). Ablation of the Sam68 RNA binding protein protects mice from age-related bone loss. PLoS Genet, 1(6): e74

[53] Ritchie W, Granjeaud S, Puthier D, Gautheret D (2008). Entropy measures quantify global splicing disorders in cancer. PLOS Comput Biol, 4(3): e1000011

[54] Rossi D J, Jamieson C H, Weissman I L (2008). Stems cells and the pathways to aging and cancer. Cell, 132(4): 681-696

[55] Salomonis N, Nelson B, Vranizan K, Pico A R, Hanspers K, Kuchinsky A, Ta L, Mercola M, Conklin B R (2009). Alternative splicing in the differentiation of human embryonic stem cells into cardiac precursors. PLOS Comput Biol, 5(11): e1000553

[56] Salomonis N, Schlieve C R, Pereira L, Wahlquist C, Colas A, Zambon A C, Vranizan K, Spindler M J, Pico A R, Cline M S, Clark T A, Williams A, Blume J E, Samal E, Mercola M, Merrill B J, Conklin B R (2010). Alternative splicing regulates mouse embryonic stem cell pluripotency and differentiation. Proc Natl Acad Sci USA, 107(23): 10514-10519

[57] Schor I E, Rascovan N, Pelisch F, Alló M, Kornblihtt A R (2009). Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing. Proc Natl Acad Sci USA, 106(11): 4325-4330

[58] Schwartz S, Ast G (2010). Chromatin density and splicing destiny: on the cross-talk between chromatin structure and splicing. EMBO J, 29(10): 1629-1636

[59] Schwartz S, Meshorer E, Ast G (2009). Chromatin organization marks exon-intron structure. Nat Struct Mol Biol, 16(9): 990-995

[60] Shibayama M, Ohno S, Osaka T, Sakamoto R, Tokunaga A, Nakatake Y, Sato M, Yoshida N (2009). Polypyrimidine tract-binding protein is essential for early mouse development and embryonic stem cell proliferation. FEBS J, 276(22): 6658-6668

[61] Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, Oberdoerffer P, Sandberg R, Oberdoerffer S (2011). CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature, 479(7371): 74-79

[62] Sims R J 3rd, Millhouse S, Chen C F, Lewis B A, Erdjument-Bromage H, Tempst P, Manley J L, Reinberg D (2007). Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing. Mol Cell, 28(4): 665-676

[63] Smith A G (2001). Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol, 17(1): 435-462

[64] Stock J K, Giadrossi S, Casanova M, Brookes E, Vidal M, Koseki H, Brockdorff N, Fisher A G, Pombo A (2007). Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nat Cell Biol, 9(12): 1428-1435

[65] Sultan M, Schulz M H, Richard H, Magen A, Klingenhoff A, Scherf M, Seifert M, Borodina T, Soldatov A, Parkhomchuk D, Schmidt D, O’Keeffe S, Haas S, Vingron M, Lehrach H, Yaspo M L (2008). A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome. Science, 321(5891): 956-960

[66] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5): 861-872

[67] Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4): 663-676

[68] Trapnell C, Williams B A, Pertea G, Mortazavi A, Kwan G, van Baren M J, Salzberg S L, Wold B J, Pachter L (2010). Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol, 28(5): 511-515

[69] Wahl M C, Will C L, Lührmann R (2009). The spliceosome: design principles of a dynamic RNP machine. Cell, 136(4): 701-718

[70] Wang E T, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore S F, Schroth G P, Burge C B (2008). Alternative isoform regulation in human tissue transcriptomes. Nature, 456(7221): 470-476

[71] Wang Z, Burge C B (2008). Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA, 14(5): 802-813

[72] Wu J Q, Habegger L, Noisa P, Szekely A, Qiu C, Hutchison S, Raha D, Egholm M, Lin H, Weissman S, Cui W, Gerstein M, Snyder M (2010). Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short, long, and paired-end sequencing. Proc Natl Acad Sci USA, 107(11): 5254-5259

[73] Wu Q, Chen X, Zhang J, Loh Y H, Low T Y, Zhang W, Zhang W, Sze S K, Lim B, Ng H H (2006). Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. J Biol Chem, 281(34): 24090-24094

[74] Yamashita Y M, Yuan H, Cheng J, Hunt A J (2010). Polarity in stem cell division: asymmetric stem cell division in tissue homeostasis. Cold Spring Harb Perspect Biol, 2(1): a001313

[75] Yeo G W, Coufal N G, Liang T Y, Peng G E, Fu X D, Gage F H (2009). An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells. Nat Struct Mol Biol, 16(2): 130-137

[76] Yeo G W, Xu X, Liang T Y, Muotri A R, Carson C T, Coufal N G, Gage F H (2007). Alternative splicing events identified in human embryonic stem cells and neural progenitors. PLOS Comput Biol, 3(10): 1951-1967

[77] Yu J, Vodyanik M A, Smuga-Otto K, Antosiewicz-Bourget J, Frane J L, Tian S, Nie J, Jonsdottir G A, Ruotti V, Stewart R, Slukvin I I, Thomson J A (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858): 1917-1920

[78] Zhang C, Zhang Z, Castle J, Sun S, Johnson J, Krainer A R, Zhang M Q (2008). Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2. Genes Dev, 22(18): 2550-2563

[79] Zhou Q, Chipperfield H, Melton D A, Wong W H (2007). A gene regulatory network in mouse embryonic stem cells. Proc Natl Acad Sci USA, 104(42): 16438-16443

Acknowledgments

We apologize to people whose work cannot be discussed in this review due to space limitation. We thank Dr. Keji Zhao and Chen laboratory members for their critical comments on this review. The work in the Chen laboratory has been supported by Research Grant No. 05-FY09-88 from the March of Dimes Foundation, the R00HD055052 NIH Pathway to Independence Award, R21 HD065089 and R01HD065816 from NICHD, the 49th Mallinckrodt Scholar Award from the Edward Mallinckrodt, Jr. Foundation, the American Federation of Aging Research, the Lucile Packard Foundation, and the Johns Hopkins University start-up funding. And I.C. is supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, USA.

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