Islet-1 induces the differentiation of mesenchymal stem cells into cardiomyocyte-like cells through the regulation of Gcn5 and DNMT-1

Yi,Qin; Xu,Hao; Yang,Ke; Wang,Yue; Tan,Bin; Tian,Jie; Zhu,Jing

doi:10.3892/mmr.2017.6343

Islet-1 induces the differentiation of mesenchymal stem cells into cardiomyocyte-like cells through the regulation of Gcn5 and DNMT-1

Authors:
- Qin Yi
- Hao Xu
- Ke Yang
- Yue Wang
- Bin Tan
- Jie Tian
- Jing Zhu
View Affiliations

Affiliations: Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China, Cardiovascular Department (Internal Medicine), Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
Published online on: March 16, 2017 https://doi.org/10.3892/mmr.2017.6343
Pages: 2511-2520
Copyright: © Yi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previous studies from this group demonstrated that insulin gene enhancer binding protein ISL-1 (Islet-1) specifically induces the differentiation of mesenchymal stem cells (MSCs) into cardiomyocyte‑like cells through histone acetylation. However, the underlying mechanisms remain unclear. In the present study, the role of the histone acetylation and DNA methylation on the regulatory mechanism of the Islet‑1 was further investigated by methylation‑specific polymerase chain reaction (PCR), chromatin immunoprecipitation quantitative PCR and western blot analysis. The results demonstrated that Islet‑1 upregulated expression of general control of amino acid biosynthesis protein 5 (Gcn5) and enhanced the binding of Gcn5 to the promoters of GATA binding protein 4 (GATA4) and NK2 homeobox 5 (Nkx2.5). In addition, Islet-1 downregulated DNA methyltransferase (DNMT)‑1 expression and reduced its binding to the GATA4 promoter. In contrast, the amount of DNMT-1 binding on Nkx2.5 did not match the expression trend. Therefore, it was concluded that Islet‑1 may influence the histone acetylation and DNA methylation of GATA4 promoter region via Gcn5 and DNMT‑1 during the MSC differentiation into cardiomyocyte-like cells, thus prompting the expression of GATA4. The Nkx2.5 was likely only affected by histone acetylation instead of DNA methylation. The present study demonstrated that Islet‑1 induces the differentiation of mesenchymal stem cells into cardiomyocyte‑like cells through a specific interaction between histone acetylation and DNA methylation on regulating GATA4.

View Figures

View References

1	Chou SH, Lin SZ, Kuo WW, Pai P, Lin JY, Lai CH, Kuo CH, Lin KH, Tsai FJ and Huang CY: Mesenchymal stem cell insights: Prospects in cardiovascular therapy. Cell Transplant. 23:513–529. 2014. View Article : Google Scholar : PubMed/NCBI
2	Kuraitis D, Ruel M and Suuronen EJ: Mesenchymal stem cells for cardiovascular regeneration. Cardiovasc Drugs Ther. 25:349–362. 2011. View Article : Google Scholar : PubMed/NCBI
3	Bianco P, Robey PG and Simmons PJ: Mesenchymal stem cells: Revisiting history, concepts and assays. Cell Stem Cell. 2:313–319. 2008. View Article : Google Scholar : PubMed/NCBI
4	Aldahmash A, Zaher W, Al-Nbaheen M and Kassem M: Human stromal (mesenchymal) stem cells: Basic biology and current clinical use for tissue regeneration. Ann Saudi Med. 32:68–77. 2012. View Article : Google Scholar : PubMed/NCBI
5	Huang L, Ma W, Ma Y, Feng D, Chen H and Cai B: Exosomes in mesenchymal stem cells, a new therapeutic strategy for cardiovascular diseases? Int J Biol Sci. 11:238–245. 2015. View Article : Google Scholar : PubMed/NCBI
6	Sheng CC, Zhou L and Hao J: Current stem cell delivery methods for myocardial repair. Biomed Res Int. 2013:5479022013. View Article : Google Scholar : PubMed/NCBI
7	Brade T, Gessert S, Kühl M and Pandur P: The amphibian second heart field: Xenopus islet-1 is required for cardiovascular development. Dev Biol. 311:297–310. 2007. View Article : Google Scholar : PubMed/NCBI
8	Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ and Chien KR: Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature. 460:113–117. 2009. View Article : Google Scholar : PubMed/NCBI
9	Yang L, Cai CL, Lin L, Qyang Y, Chung C, Monteiro RM, Mummery CL, Fishman GI, Cogen A and Evans S: Isl1Cre reveals a common Bmp pathway in heart and limb development. Development. 133:1575–1585. 2006. View Article : Google Scholar : PubMed/NCBI
10	Laugwitz KL, Moretti A, Caron L, Nakano A and Chien KR: Islet1 cardiovascular progenitors: A single source for heart lineages? Development. 135:193–205. 2008. View Article : Google Scholar : PubMed/NCBI
11	Nakano A, Nakano H and Chien KR: Multipotent islet-1 cardiovascular progenitors in development and disease. Cold Spring Harb Symp Quant Biol. 73:297–306. 2008. View Article : Google Scholar : PubMed/NCBI
12	Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J and Evans S: Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 5:877–889. 2003. View Article : Google Scholar : PubMed/NCBI
13	Yin N, Lu R, Lin J, Zhi S, Tian J and Zhu J: Islet-1 promotes the cardiac-specific differentiation of mesenchymal stem cells through the regulation of histone acetylation. Int J Mol Med. 33:1075–1082. 2014.PubMed/NCBI
14	Li L, Zhu J, Tian J, Liu X and Feng C: A role for Gcn5 in cardiomyocyte differentiation of rat mesenchymal stem cells. Mol Cell Biochem. 345:309–316. 2010. View Article : Google Scholar : PubMed/NCBI
15	Peng C, Zhu J, Sun HC, Huang XP, Zhao WA, Zheng M, Liu LJ and Tian J: Inhibition of histone H3K9 acetylation by anacardic acid can correct the over-expression of Gata4 in the hearts of fetal mice exposed to alcohol during pregnancy. PLoS One. 9:e1041352014. View Article : Google Scholar : PubMed/NCBI
16	Bird A: DNA methylation patterns and epigenetic memory. Genes Dev. 16:6–21. 2002. View Article : Google Scholar : PubMed/NCBI
17	Ting AH, Jair KW, Suzuki H, Yen RW, Baylin SB and Schuebel KE: Mammalian DNA methyltransferase 1: Inspiration for new directions. Cell Cycle. 3:1024–1026. 2004. View Article : Google Scholar : PubMed/NCBI
18	Wu Y, Strawn E, Basir Z, Halverson G and Guo SW: Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A and DNMT3B in women with endometriosis. Fertil Steril. 87:24–32. 2007. View Article : Google Scholar : PubMed/NCBI
19	Luczak MW, Roszak A, Pawlik P, Kędzia H, Kędzia W, Malkowska-Walczak B, Lianeri M and Jagodziński PP: Transcriptional analysis of CXCR4, DNMT3A, DNMT3B and DNMT1 gene expression in primary advanced uterine cervical carcinoma. Int J Oncol. 40:860–866. 2012.PubMed/NCBI
20	Liao J, Karnik R, Gu H, Ziller MJ, Clement K, Tsankov AM, Akopian V, Gifford CA, Donaghey J, Galonska C, et al: Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat Genet. 47:469–478. 2015. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of reltive gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Fu L, Xia Y, He J, Liu X, Chen X, Wang Y and Ding Y: Data analysis and its analytical softs application on DNA methylation in tumor research. Zhong Qing Yi Xue Bian Ji Bu. 41:1719–1721, 1726. 2012.(In Chinese).
23	Xu H, Yi Q, Yang C, Wang Y, Tian J and Zhu J: Histone modifications interact with DNA methylation at the GATA4 promoter during differentiation of mesenchymal stem cells into cardiomyocyte-like cells. Cell Prolif. 49:315–329. 2016. View Article : Google Scholar : PubMed/NCBI
24	Kawamura T, Ono K, Morimoto T, Wada H, Hirai M, Hidaka K, Morisaki T, Heike T, Nakahata T, Kita T and Hasegawa K: Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes. J Biol Chem. 280:19682–19688. 2005. View Article : Google Scholar : PubMed/NCBI
25	Pasini A, Bonafè F, Govoni M, Guarnieri C, Morselli PG, Sharma HS, Caldarera CM, Muscari C and Giordano E: Epigenetic signature of early cardiac regulatory genes in native human adipose-derived stem cells. Cell Biochem Biophys. 67:255–262. 2013. View Article : Google Scholar : PubMed/NCBI
26	Zhang H and Wang ZZ: Mechanisms that mediate stem cell self-renewal and differentiation. J Cell Biochem. 103:709–718. 2008. View Article : Google Scholar : PubMed/NCBI
27	Ohtani K and Dimmeler S: Epigenetic regulation of cardiovascular differentiation. Cardiovasc Res. 90:404–412. 2011. View Article : Google Scholar : PubMed/NCBI
28	Spivakov M and Fisher AG: Epigenetic signatures of stem-cell identity. Nat Rev Genet. 8:263–271. 2007. View Article : Google Scholar : PubMed/NCBI
29	Hawkins RD, Hon GC, Lee LK, Ngo Q, Lister R, Pelizzola M, Edsall LE, Kuan S, Luu Y, Klugman S, et al: Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. 6:479–491. 2010. View Article : Google Scholar : PubMed/NCBI
30	Horikoshi M: Histone acetylation: From code to web and router via intrinsically disordered regions. Curr Pharm Des. 19:5019–5042. 2013. View Article : Google Scholar : PubMed/NCBI
31	Oligny LL: Human molecular embryogenesis: An overview. Pediatr Dev Pathol. 4:324–343. 2001. View Article : Google Scholar : PubMed/NCBI
32	Sadoul K, Boyault C, Pabion M and Khochbin S: Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie. 90:306–312. 2008. View Article : Google Scholar : PubMed/NCBI
33	Kurdistani SK and Grunstein M: Histone acetylation and deacetylation in yeast. Nat Rev Mol Cell Biol. 4:276–284. 2003. View Article : Google Scholar : PubMed/NCBI
34	Hu Z, Song N, Zheng M, Liu X, Liu Z, Xing J, Ma J, Guo W, Yao Y, Peng H, et al: Histone acetyltransferase GCN5 is essential for heat stress-responsive gene activation and thermotolerance in arabidopsis. Plant J. 84:1178–1191. 2015. View Article : Google Scholar : PubMed/NCBI
35	Kuo YM and Andrews AJ: Quantitating the specificity and selectivity of Gcn5-mediated acetylation of histone H3. PLoS One. 8:e548962013. View Article : Google Scholar : PubMed/NCBI
36	Kornacki JR, Stuparu AD and Mrksich M: Acetyltransferase p300/CBP associated factor (PCAF) regulates crosstalk-dependent acetylation of histone H3 by distal site recognition. ACS Chem Biol. 10:157–164. 2015. View Article : Google Scholar : PubMed/NCBI
37	Zheng M, Zhu J, Lu T, Liu L, Sun H, Liu Z and Tian J: P300-mediated histone acetylation is essential for the regulation of GATA4 and MEF2C by BMP2 in H9c2 cells. Cardiovasc Toxicol. 13:316–322. 2013. View Article : Google Scholar : PubMed/NCBI
38	Nagre NN, Subbanna S, Shivakumar M, Psychoyos D and Basavarajappa BS: CB1-receptor knockout neonatal mice are protected against ethanol-induced impairments of DNMT1, DNMT3A and DNA methylation. J Neurochem. 132:429–442. 2015. View Article : Google Scholar : PubMed/NCBI
39	Arakawa Y, Watanabe M, Inoue N, Sarumaru M, Hidaka Y and Iwatani Y: Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease. Clin Exp Immunol. 170:194–201. 2012. View Article : Google Scholar : PubMed/NCBI
40	Subramaniam D, Thombre R, Dhar A and Anant S: DNA methyltransferases: A novel target for prevention and therapy. Front Oncol. 4:802014. View Article : Google Scholar : PubMed/NCBI
41	Minardi D, Lucarini G, Filosa A, Zizzi A, Milanese G, Polito M Jr, Polito M, Di Primio R, Montironi R and Muzzonigro G: Do DNA-methylation and histone acetylation play a role in clear cell renal carcinoma? Analysis of radical nephrectomy specimens in a long-term follow-up. Int J Immunopathol Pharmacol. 24:149–158. 2011. View Article : Google Scholar : PubMed/NCBI
42	Wu LP, Wang X, Li L, Zhao Y, Lu S, Yu Y, Zhou W, Liu X, Yang J, Zheng Z, et al: Histone deacetylase inhibitor depsipeptide activates silenced genes through decreasing both CpG and H3K9 methylation on the promoter. Mol Cell Biol. 28:3219–3235. 2008. View Article : Google Scholar : PubMed/NCBI