Abstract
The process of identifying sets of transcription factors that can induce a cell conversion can be time-consuming and expensive. To help alleviate this, a number of computational tools have been developed which integrate gene expression data with molecular interaction networks in order to predict these factors. One such approach is Mogrify, an algorithm which ranks transcriptions factors based on their regulatory influence in different cell types and tissues. These ranks are then used to identify a nonredundant set of transcription factors to promote cell conversion between any two cell types/tissues. Here we summarize the important concepts and data sources that were used in the implementation of this approach. Furthermore, we describe how the associated web resource (www.mogrify.net) can be used to tailor predictions to specific experimental scenarios, for instance, limiting the set of possible transcription factors and including domain knowledge. Finally, we describe important considerations for the effective selection of reprogramming factors. We envision that such data-driven approaches will become commonplace in the field, rapidly accelerating the progress in stem cell biology.
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10 July 2019
This chapter was published without including the “Conflict of Interest” section given by the author along with the corrected proof.
References
D’Alessio AC, Fan ZP, Wert KJ, Baranov P, Cohen MA, Saini JS, Cohick E, Charniga C, Dadon D, Hannett NM et al (2015) A systematic approach to identify candidate transcription factors that control cell identity. Stem Cell Rep 5:763–775
Cahan P, Li H, Morris SA, Lummertz da Rocha E, Daley GQ, Collins JJ (2014) CellNet: network biology applied to stem cell engineering. Cell 158:903–915
Rackham OJL, Firas J, Fang H, Oates ME, Holmes ML, Knaupp AS, FANTOM Consortium, Suzuki H, Nefzger CM, Daub CO et al (2016) A predictive computational framework for direct reprogramming between human cell types. Nat Genet 48:331–335
Thomas DB (1971) The differentiation of transplanted haematopoietic cells derived from bone marrow, spleen and fetal liver. J Anat 110:297–306
Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A 78:7634–7638
Briggs R, King TJ (1952) Transplantation of living nuclei from blastula cells into enucleated frogs’ eggs. Proc Natl Acad Sci U S A 38:455–463
Campbell KH, McWhir J, Ritchie WA, Wilmut I (1996) Sheep cloned by nuclear transfer from a cultured cell line. Nature 380:64–66
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
Lassar AB, Paterson BM, Weintraub H (1986) Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts. Cell 47:649–656
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM (2009) Initiation of myoblast to brown fat switch by a PRDM16–C/EBP-β transcriptional complex. Nature 460:1154
Caiazzo M, Giannelli S, Valente P, Lignani G, Carissimo A, Sessa A, Colasante G, Bartolomeo R, Massimino L, Ferroni S et al (2015) Direct conversion of fibroblasts into functional astrocytes by defined transcription factors. Stem Cell Rep 4:25–36
Muraoka N, Yamakawa H, Miyamoto K, Sadahiro T, Umei T, Isomi M, Nakashima H, Akiyama M, Wada R, Inagawa K et al (2014) MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J 33:1565–1581
Islas JF, Liu Y, Weng K-C, Robertson MJ, Zhang S, Prejusa A, Harger J, Tikhomirova D, Chopra M, Iyer D et al (2012) Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. Proc Natl Acad Sci U S A 109:13016–13021
Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T, Umei T, Kaneda R, Suzuki T, Kamiya K et al (2013) Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci U S A 110:12667–12672
Nam Y-J, Song K, Luo X, Daniel E, Lambeth K, West K, Hill JA, DiMaio JM, Baker LA, Bassel-Duby R et al (2013) Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A 110:5588–5593
Fu J-D, Stone NR, Liu L, Spencer CI, Qian L, Hayashi Y, Delgado-Olguin P, Ding S, Bruneau BG, Srivastava D (2013) Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Rep 1:235–247
Ishii R, Kami D, Toyoda M, Makino H, Gojo S, Ishii T, Umezawa A (2012) Placenta to cartilage: direct conversion of human placenta to chondrocytes with transformation by defined factors. Mol Biol Cell 23:3511–3521
Liu X, Li F, Stubblefield EA, Blanchard B, Richards TL, Larson GA, He Y, Huang Q, Tan A-C, Zhang D et al (2012) Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Res 22:321–332
Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Björklund A, Lindvall O, Jakobsson J, Parmar M (2011) Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A 108:10343–10348
Wong WT, Cooke JP (2016) Therapeutic transdifferentiation of human fibroblasts into endothelial cells using forced expression of lineage-specific transcription factors. J Tissue Eng 7:2041731416628329
Nouri M, Deezagi A, Ebrahimi M (2016) Reprogramming of human peripheral blood monocytes to erythroid lineage by blocking of the PU-1 gene expression. Ann Hematol 95:549–556
Ho S-M, Hartley BJ, Tcw J, Beaumont M, Stafford K, Slesinger PA, Brennand KJ (2016) Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells. Methods 101:113–124
Wamaitha SE, del Valle I, Cho LTY, Wei Y, Fogarty NME, Blakeley P, Sherwood RI, Ji H, Niakan KK (2015) Gata6 potently initiates reprograming of pluripotent and differentiated cells to extraembryonic endoderm stem cells. Genes Dev 29:1239–1255
Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC et al (2011) Induction of human neuronal cells by defined transcription factors. Nature 476:220–223
Sandler VM, Lis R, Liu Y, Kedem A, James D, Elemento O, Butler JM, Scandura JM, Rafii S (2014) Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Nature 511:312–318
Szabo E, Rampalli S, Risueño RM, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M (2010) Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468:521–526
Du Y, Wang J, Jia J, Song N, Xiang C, Xu J, Hou Z, Su X, Liu B, Jiang T et al (2014) Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell 14:394–403
Wang XL, Hu P, Guo XR, Yan D, Yuan Y, Yan SR, Li DS (2014) Reprogramming human umbilical cord mesenchymal stromal cells to islet-like cells with the use of in vitro-synthesized pancreatic-duodenal homebox 1 messenger RNA. Cytotherapy 16:1519–1527
Rapino F, Robles EF, Richter-Larrea JA, Kallin EM, Martinez-Climent JA, Graf T (2013) C/EBPα induces highly efficient macrophage transdifferentiation of B lymphoma and leukemia cell lines and impairs their tumorigenicity. Cell Rep 3:1153–1163
Victor MB, Richner M, Hermanstyne TO, Ransdell JL, Sobieski C, Deng P-Y, Klyachko VA, Nerbonne JM, Yoo AS (2014) Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts. Neuron 84:311–323
Yang R, Zheng Y, Li L, Liu S, Burrows M, Wei Z, Nace A, Herlyn M, Cui R, Guo W et al (2014) Direct conversion of mouse and human fibroblasts to functional melanocytes by defined factors. Nat Commun 5:5807
Park H-W, Cho J-S, Park C-K, Jung SJ, Park C-H, Lee S-J, Oh SB, Park Y-S, Chang M-S (2012) Directed induction of functional motor neuron-like cells from genetically engineered human mesenchymal stem cells. PLoS One 7:e35244
Lattanzi L, Salvatori G, Coletta M, Sonnino C, Cusella De Angelis MG, Gioglio L, Murry CE, Kelly R, Ferrari G, Molinaro M et al (1998) High efficiency myogenic conversion of human fibroblasts by adenoviral vector-mediated MyoD gene transfer. An alternative strategy for ex vivo gene therapy of primary myopathies. J Clin Invest 101:2119–2128
Hendry CE, Vanslambrouck JM, Ineson J, Suhaimi N, Takasato M, Rae F, Little MH (2013) Direct transcriptional reprogramming of adult cells to embryonic nephron progenitors. J Am Soc Nephrol 24:1424–1434
Kim YJ, Lim H, Li Z, Oh Y, Kovlyagina I, Choi IY, Dong X, Lee G (2014) Generation of multipotent induced neural crest by direct reprogramming of human postnatal fibroblasts with a single transcription factor. Cell Stem Cell 15:497–506
Lujan E, Chanda S, Ahlenius H, Südhof TC, Wernig M (2012) Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci U S A 109:2527–2532
Mitchell RR, Szabo E, Benoit YD, Case DT, Mechael R, Alamilla J, Lee JH, Fiebig-Comyn A, Gillespie DC, Bhatia M (2014) Activation of neural cell fate programs toward direct conversion of adult human fibroblasts into tri-potent neural progenitors using OCT-4. Stem Cells Dev 23:1937–1946
Lee J-H, Mitchell RR, McNicol JD, Shapovalova Z, Laronde S, Tanasijevic B, Milsom C, Casado F, Fiebig-Comyn A, Collins TJ et al (2015) Single transcription factor conversion of human blood fate to NPCs with CNS and PNS developmental capacity. Cell Rep 11:1367–1376
Liao W, Huang N, Yu J, Jares A, Yang J, Zieve G, Avila C, Jiang X, Zhang X-B, Ma Y (2015) Direct conversion of cord blood CD34+ cells into neural stem cells by OCT4. Stem Cells Transl Med 4:755–763
Zhao P, Zhu T, Lu X, Zhu J, Li L (2015) Neurogenin 2 enhances the generation of patient-specific induced neuronal cells. Brain Res 1615:51–60
Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G (2014) In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell 14:188–202
Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–1041
Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, Ding S (2011) Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9:113–118
Hsu Y-C, Chen S-L, Wang Y-J, Chen Y-H, Wang D-Y, Chen L, Chen C-H, Chen H-H, Chiu I-M (2014) Signaling adaptor protein SH2B1 enhances neurite outgrowth and accelerates the maturation of human induced neurons. Stem Cells Transl Med 3:713–722
Zhou C, Gu H, Fan R, Wang B, Lou J (2015) MicroRNA 302/367 cluster effectively facilitates direct reprogramming from human fibroblasts into functional neurons. Stem Cells Dev 24:2746–2755
Karow M, Sánchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascón S, Khan MA, Lie DC, Dellavalle A et al (2012) Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell 11:471–476
Yamamoto K, Kishida T, Sato Y, Nishioka K, Ejima A, Fujiwara H, Kubo T, Yamamoto T, Kanamura N, Mazda O (2015) Direct conversion of human fibroblasts into functional osteoblasts by defined factors. Proc Natl Acad Sci U S A 112:6152–6157
Sangan CB, Jover R, Heimberg H, Tosh D (2015) In vitro reprogramming of pancreatic alpha cells towards a beta cell phenotype following ectopic HNF4α expression. Mol Cell Endocrinol 399:50–59
Berneman-Zeitouni D, Molakandov K, Elgart M, Mor E, Fornoni A, Domínguez MR, Kerr-Conte J, Ott M, Meivar-Levy I, Ferber S (2014) The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation. PLoS One 9:e87812
Mauda-Havakuk M, Litichever N, Chernichovski E, Nakar O, Winkler E, Mazkereth R, Orenstein A, Bar-Meir E, Ravassard P, Meivar-Levy I et al (2011) Ectopic PDX-1 expression directly reprograms human keratinocytes along pancreatic insulin-producing cells fate. PLoS One 6:e26298
Chiou S-H, Chen S-J, Chang Y-L, Chen Y-C, Li H-Y, Chen D-T, Wang H-H, Chang C-M, Chen Y-J, Ku H-H (2011) MafA promotes the reprogramming of placenta-derived multipotent stem cells into pancreatic islets-like and insulin+ cells. J Cell Mol Med 15:612–624
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 131:861–872
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920
Deng W, Cao X, Chen J, Zhang Z, Yu Q, Wang Y, Shao G, Zhou J, Gao X, Yu J et al (2015) MicroRNA replacing oncogenic Klf4 and c-Myc for generating iPS cells via cationized Pleurotus eryngii polysaccharide-based nanotransfection. ACS Appl Mater Interfaces 7:18957–18966
Kim JB, Greber B, Araúzo-Bravo MJ, Meyer J, Park KI, Zaehres H, Schöler HR (2009) Direct reprogramming of human neural stem cells by OCT4. Nature 461:649–643
Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D et al (2009) Oct4-induced pluripotency in adult neural stem cells. Cell 136:411–419
Zhang K, Liu G-H, Yi F, Montserrat N, Hishida T, Esteban CR, Izpisua Belmonte JC (2014) Direct conversion of human fibroblasts into retinal pigment epithelium-like cells by defined factors. Protein Cell 5:48–58
Li P, Sun X, Ma Z, Liu Y, Jin Y, Ge R, Hao L, Ma Y, Han S, Sun H et al (2016) Transcriptional reactivation of OTX2, RX1 and SIX3 during reprogramming contributes to the generation of RPE cells from human iPSCs. Int J Biol Sci 12:505–517
Son EY, Ichida JK, Wainger BJ, Toma JS, Rafuse VF, Woolf CJ, Eggan K (2011) Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9:205–218
Bredenkamp N, Ulyanchenko S, O’Neill KE, Manley NR, Vaidya HJ, Blackburn CC (2014) An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat Cell Biol 16:902–908
Chen Y, Wang K, Gong YG, Khoo SK, Leach R (2013) Roles of CDX2 and EOMES in human induced trophoblast progenitor cells. Biochem Biophys Res Commun 431:197–202
Ginsberg M, James D, Ding B-S, Nolan D, Geng F, Butler JM, Schachterle W, Pulijaal VR, Mathew S, Chasen ST et al (2012) Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression. Cell 151:559–575
Anders S (2010) Analysing RNA-Seq data with the DESeq package. Mol Biol. Available at: http://owl.fish.washington.edu/halfshell/bu-git-repos/LabDocs/code/DESeq/MANUAL_DESeq.pdf
Kulakovskiy IV, Medvedeva YA, Schaefer U, Kasianov AS, Vorontsov IE, Bajic VB, Makeev VJ (2013) HOCOMOCO: a comprehensive collection of human transcription factor binding sites models. Nucleic Acids Res 41:D195–D202
Yevshin I, Sharipov R, Valeev T, Kel A, Kolpakov F (2017) GTRD: a database of transcription factor binding sites identified by ChIP-seq experiments. Nucleic Acids Res 45:D61–D67
Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J et al (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133:1106–1117
Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P et al (2017) The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res 45:D362–D368
FANTOM Consortium and the RIKEN PMI and CLST (DGT), Forrest ARR, Kawaji H, Rehli M, Baillie JK, de Hoon MJL, Haberle V, Lassmann T, Kulakovskiy IV, Lizio M et al (2014) A promoter-level mammalian expression atlas. Nature 507:462–470
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT et al (2000) Gene ontology: tool for the unification of biology. Nat Genet 25:25
The Gene Ontology Consortium (2017) Expansion of the gene ontology knowledgebase and resources. Nucleic Acids Res 45:D331–D338
Wingender E, Schoeps T, Haubrock M, Dönitz J (2015) TFClass: a classification of human transcription factors and their rodent orthologs. Nucleic Acids Res 43:D97–D102
Fulton DL, Sundararajan S, Badis G, Hughes TR, Wasserman WW, Roach JC, Sladek R (2009) TFCat: the curated catalog of mouse and human transcription factors. Genome Biol 10:R29
Balwierz PJ, Pachkov M, Arnold P, Gruber AJ, Zavolan M, van Nimwegen E (2014) ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs. Genome Res 24:869–884
Cole MF, Johnstone SE, Newman JJ, Kagey MH, Young RA (2008) Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 22:746–755
Yuri S, Fujimura S, Nimura K, Takeda N, Toyooka Y, Fujimura Y-I, Aburatani H, Ura K, Koseki H, Niwa H et al (2009) Sall4 is essential for stabilization, but not for pluripotency, of embryonic stem cells by repressing aberrant trophectoderm gene expression. Stem Cells 27:796–805
Masui S, Ohtsuka S, Yagi R, Takahashi K, Ko MSH, Niwa H (2008) Rex1/Zfp42 is dispensable for pluripotency in mouse ES cells. BMC Dev Biol 8:45
Xin M, Olson EN, Bassel-Duby R (2013) Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat Rev Mol Cell Biol 14:529–541
Vollmar B, Menger MD (2009) The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 89:1269–1339
Conflict of Interest
Owen Rackham, Julian Gough and Jose Polo are founders and directors of Cell Mogrify Ltd. The other authors do not declare any conflict of interest.
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Ouyang, J.F., Kamaraj, U.S., Polo, J.M., Gough, J., Rackham, O.J.L. (2019). Molecular Interaction Networks to Select Factors for Cell Conversion. In: Cahan, P. (eds) Computational Stem Cell Biology. Methods in Molecular Biology, vol 1975. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9224-9_16
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