Induced pluripotent stem cells reprogramming: Epigenetics and applications in the regenerative medicine

Gomes, Kátia Maria Sampaio; Costa, Ismael Cabral; Santos, Jeniffer Farias dos; Dourado, Paulo Magno Martins; Forni, Maria Fernanda; Ferreira, Julio Cesar Batista

doi:10.1590/1806-9282.63.02.180

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REVIEW ARTICLES • Rev. Assoc. Med. Bras. 63 (2) • Feb 2017 • https://doi.org/10.1590/1806-9282.63.02.180 copy

Induced pluripotent stem cells reprogramming: Epigenetics and applications in the regenerative medicine

Células-tronco de pluripotência induzida: papel da epigenética na reprogramação e sua aplicabilidade clínica

Authorship SCIMAGO INSTITUTIONS RANKINGS

Summary

Induced pluripotent stem cells (iPSCs) are somatic cells reprogrammed into an embryonic-like pluripotent state by the expression of specific transcription factors. iPSC technology is expected to revolutionize regenerative medicine in the near future. Despite the fact that these cells have the capacity to self-renew, they present low efficiency of reprogramming. Recent studies have demonstrated that the previous somatic epigenetic signature is a limiting factor in iPSC performance. Indeed, the process of effective reprogramming involves a complete remodeling of the existing somatic epigenetic memory, followed by the establishment of a "new epigenetic signature" that complies with the new type of cell to be differentiated. Therefore, further investigations of epigenetic modifications associated with iPSC reprogramming are required in an attempt to improve their self-renew capacity and potency, as well as their application in regenerative medicine, with a new strategy to reduce the damage in degenerative diseases. Our review aimed to summarize the most recent findings on epigenetics and iPSC, focusing on DNA methylation, histone modifications and microRNAs, highlighting their potential in translating cell therapy into clinics.

Keywords:
induced pluripotent stem cells; regenerative medicine; cell reprogramming; epigenetics; histones; microRNAs

Authors	Year	Species	Type of cell	Technology	Epigenetic changes	Results
Mikkelsen et al.³³33 Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008; 454(7200):49-55.	2008	Mice	Fibroblasts	5-azacytidine (AZA)	Inhibitor of DNA methyltransferase	Promotes the demethylation of pluripotency genes
Mikkelsen et al.³³33 Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008; 454(7200):49-55.	2008	Mice	Fibroblasts	shRNA/siRNA	Reduced expression of DNMT1 using siRNA/shRNA	Demethylation and complete reprogramming of cells
Popp et al.²⁸28 Popp C, Dean W, Feng S, Cokus SJ, Andrews S, Pellegrini M, et al. Genomewide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature. 2010; 463(7284):1101-5.	2010	Mice	Embryonic	AID	DNA demethylation	Clears all standard demethylation of the genome
Doege et al.²⁹29 Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R, et al. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature. 2012; 488(7413):652-5.	2012	Mice	Fibroblasts	Tet2	Generation of 5-hydroxymethylcytosine (5hmC) through the oxidation of 5mC	Hydroxylation of pluripotency sites (Nanog and Esrrb) favoring a greater number of iPSCs
Costa et al.³⁰30 Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, et al. NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature. 2013; 495(7441):370-4.	2013	Mice	Embryonic	Tet1/Tet2	Physical interaction with Nanog	Hydroxylation of pluripotency sites (Oct4 and Esrrb)
Gao et al.³¹31 Gao Y, Chen J, Li K, Wu T, Huang B, Liu W, et al. Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell. 2013; 12(4):453-69.	2013	Mice	Fibroblasts	Tet1	DNA demethylation and activation of Oct4	Better induction of pluripotency

Authors	Year	Species	Type of cell	Technology	Epigenetic changes	Results
Huangfu et al.⁴⁴44 Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol. 2008; 26(7):795-7.	2008	Mice	Fibroblasts	VPA/TSA/SAHA	Inhibitor of histone deacetylation	Prevents histone deacetylation, increasing reprogramming efficiency by more than 100X compared to OSKM
Shi et al.⁴³43 Shi Y, Desponts C, Do JT, Hahm HS, Schöler HR, Ding S. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell. 2008; 3(5):568-74.	2008	Mice	Fibroblasts	BIX-01294	G9a methyltransferase inhibitor	Reduces histone H3K9 methylation, facilitating transcription. Improves reprogramming efficiency compared to Oct4 and Klf4
Esteban et al.³⁵35 Esteban MA, Wang T, Qin B, Yang J, Qin D, Cai J, et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell. 2010; 6(1):71-9.	2010	Humans	Fibroblasts	Vitamin C	Nanog promoter, Oct4/ Histone demethylation	Decreases senescence during reprogramming
Liang et al.⁴⁶46 Liang G, Taranova O, Xia K, Zhang Y. Butyrate promotes induced pluripotent stem cell generation. J Biol Chem. 2010; 285(33):25516-21.	2010	Mice	Fibroblasts	Sodium butyrate	Histone deacetylase (HDAC) inhibitor	Facilitates reprogramming mediated by c-Myc
Liang et al.⁴⁸48 Liang G, He J, Zhang Y. Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat Cell Biol. 2012; 14(5):457-66.	2012	Mice	Fibroblasts	Lentivirus increasing the expression of Kdm2b	Activation of genes in the initial phase of reprogramming	Decreased H3K36me2 levels, contributing to reprogramming
Onder et al.⁴⁷47 Onder TT, Kara N, Cherry A, Sinha AU, Zhu N, Bernt KM, et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature. 2012; 483(7391):598-602.	2012	Mice	Fibroblasts	epz004777	DOT1L inhibitor (Histone methyltransferase specific for H3K79)	With the reduction of DOT1L, a reduction in the methylation of H3K79 occurs, improving the reprogramming by increasing transcription factors such as Nanog and Lin28
Chen et al.⁴⁵45 Chen J, Liu H, Liu J, Qi J, Wei B, Yang J, et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet. 2013; 45(1):34-42.	2013	Mice	Fibroblasts	Vitamin C	Increases Kdm3 and Kdm4 - Lysine-specific demethylase	Reduces H3K9me2 and H3K9me3, important early in the reprogramming of iPSCs
Hou et al.⁴²42 Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science. 2013; 341(6146):651-4.	2013	Mice	Fibroblasts	3-deazaneplanocin A (Dznep)	Histone methyltransferase inhibitor	Better reprogramming occurs with inhibition of histone methyltransferase by preventing methylation in the arginine and lysine residues of histones

Authors	Year	miRNA	Species	Type of cell	Mechanism of action	Results
Judson et al.⁵⁴54 Judson RL, Babiarz JE, Venere M, Blelloch R. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol. 2009; 27(5):459-61.	2009	290-295	Mice	Fibroblast	Blocks p21, leading to increased cell cycle proteins	Promotes the G1-S phase transition (proliferation), indirectly activating pluripotency factors
Li and He⁵⁰50 Li MA, He L. microRNAs as novel regulators of stem cell pluripotency and somatic cell reprogramming. Bioessays. 2012; 34(8):670-80.	2012	Let-7	Mice	Embryonic stem cell	Reduced CyclinD/Cdk4 regulation	Blocks G1-S phase
Subramanyam et al.; Lin et al.⁵⁵55 Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, et al. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol. 2011; 29(5):443-8.^,⁵⁶56 Lin SL, Chang DC, Lin CH, Ying SY, Leu D, Wu DTS. Regulation of somatic cell reprogramming through inducible mir-302 expression. Nucleic Acids Res. 2011; 39(3):1054-65.	2011	302-367	Mice	Fibroblast	Inhibits TGFII-β	Promotes MET
Choi et al.⁶³63 Choi YJ, Lin C, Ho JJ, He X, Okada N, Bu P, et al. miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol. 2011; 13(11):1353-60.	2011	34a and 34b/c	Mice	Fibroblast	Reduced regulation of p21 and p53	Indirectly blocks pluripotency factors
Li et al.⁶¹61 Li Z, Dang J, Chang K, Rana TM. MicroRNA-mediated regulation of extracellular matrix formation modulates somatic cell reprogramming. RNA. 2014; 20(12):1900-15.	2014	135b	Mice	Fibroblast	Reduced expression of TGF-β, Igfbp5, and Wisp1	Promotes MET
Zare et al.⁴⁹49 Zare M, Soleimani M, Akbarzadeh A, Bakhshandeh B, Aghaee-Bakhtiari SH, Zarghami N. A novel protocol to differentiate induced pluripotent stem cells by neuronal microRNAs to provide a suitable cellular model. Chem Biol Drug Des. 2015; 86(2):232-8.	2015	124-128	Humans	Fibroblast	Regulate the development of neurons	Promotes the migration, maturation and differentiation of neurons, maintaining adequate gene expression and repressing unwanted genes

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[1] *Correspondence: Departamento de Anatomia, ICB III/USP. Address: Av. Prof. Lineu Prestes, 2415, Cidade Universitária São Paulo, SP - Brazil. Postal code: 05508-000. kmsgomes@gmail.com