Small-molecule inhibitors and microRNAs (miRNAs) are two newly emerging classes of tools for optimizing induced pluripotent stem cell (iPSC) generation. We report here that sodium butyrate (NaB), a small-molecule inhibitor of histone deacetylases (HDACs), upregulates transcriptional levels of the miR-302/367 cluster by enhancing Oct4 transcriptional activity at the miR-302/367 cluster promoter. NaB does not affect the OCT4 DNA-binding domain; instead it enhances transactivity of the OCT4 transactivation domains. We elucidate that OCT4 transcriptional activity is usually dampened by its associated HDACs in cells and can be derepressed by NaB by impairing the interaction between Oct4 and HDACs, which leads to an elevated expression of the miR-302/367 cluster. Our new findings suggest a novel molecular mechanism for NaB in promoting somatic cell reprogramming via the miR-302/367 cluster.
Get full access to this article
View all access options for this article.
References
1.
Anokye-DansoF., TrivediC.M., JuhrD., GuptaM., CuiZ., TianY., ZhangY., YangW., GruberP.J., EpsteinJ.A., and MorriseyE.E. (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell, 8, 376–388.
BrehmA., OhboK., and ScholerH. (1997). The carboxy-terminal transactivation domain of Oct-4 acquires cell specificity through the POU domain. Mol. Cell. Biol., 17, 154–162.
4.
CardD.A., HebbarP.B., LiL., TrotterK.W., KomatsuY., MishinaY., and ArcherT.K. (2008). Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Mol. Cell. Biol., 28, 6426–6438.
5.
KajiK., CaballeroI.M., MacLeodR., NicholsJ., WilsonV.A., and HendrichB. (2006). The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat. Cell Biol., 8, 285–292.
6.
KimJ.B., SebastianoV., WuG., Arauzo-BravoM.J., SasseP., GentileL., KoK., RuauD., EhrichM., van den BoomD., MeyerJ., HübnerK., BernemannC., OrtmeierC., ZenkeM., FleischmannB.K., ZaehresH., and SchölerH.R. (2009). Oct4-induced pluripotency in adult neural stem cells. Cell, 136, 411–419.
7.
LiangG., TaranovaO., XiaK., and ZhangY. (2010). Butyrate promotes induced pluripotent stem cell generation. J. Biol. Chem., 285, 25516–25521.
8.
LiangJ., WanM., ZhangY., GuP., XinH., JungS.Y., QinJ., WongJ., CooneyA.J., LiuD., and SongyangZ. (2008). Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat. Cell Biol., 10, 731–739.
9.
LiaoB., BaoX., LiuL., FengS., ZovoilisA., LiuW., XueY., CaiJ., GuoX., QinB., ZhangR., WuJ., LaiL., TengM., NiuL., ZhangB., EstebanM.A., and PeiD. (2011). MicroRNA cluster 302-367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. J. Biol. Chem., 286, 17359–17364.
10.
LimH.Y., DoH.J., LeeW.Y., KimD.K., SeoH.G., ChungH.J., ParkJ.K., ChangW.K., KimJ.H., and KimJ.H. (2009). Implication of human OCT4 transactivation domains for self-regulatory transcription. Biochem. Biophys. Res. Commun., 385, 148–153.
11.
LinS.L., ChangD.C., LinC.H., YingS.Y., LeuD., and WuD.T. (2011). Regulation of somatic cell reprogramming through inducible mir-302 expression. Nucleic Acids Res., 39, 1054–1065.
12.
LinT., AmbasudhanR., YuanX., LiW., HilcoveS., AbujarourR., LinX., HahmH.S., HaoE., HayekA., and DingS. (2009). A chemical platform for improved induction of human iPSCs. Nat. Methods, 6, 805–808.
13.
LipchinaI., StuderL., and BetelD. (2012). The expanding role of miR-302-367 in pluripotency and reprogramming. Cell Cycle, 11, 1517–1523.
14.
LowryW.E., RichterL., YachechkoR., PyleA.D., TchieuJ., SridharanR., ClarkA.T., and PlathK. (2008). Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl. Acad. Sci. USA, 105, 2883–2888.
15.
MaliP., ChouB.K., YenJ., YeZ., ZouJ., DoweyS., BrodskyR.A., OhmJ.E., YuW., BaylinS.B., YusaK., BradleyA., MeyersD.J., MukherjeeC., ColeP.A., and ChengL. (2010). Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells, 28, 713–720.
16.
MeissnerA., WernigM., and JaenischR. (2007). Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat. Biotechnol., 25, 1177–1181.
17.
MiyoshiN., IshiiH., NaganoH., HaraguchiN., DewiD.L., KanoY., NishikawaS., TanemuraM., MimoriK., TanakaF., SaitoT., NishimuraJ., TakemasaI., MizushimaT., IkedaM., YamamotoH., SekimotoM., DokiY., and MoriM. (2011). Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell, 8, 633–638.
18.
ParkI.H., ZhaoR., WestJ.A., YabuuchiA., HuoH., InceT.A., LerouP.H., LenschM.W., and DaleyG.Q. (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature, 451, 141–146.
19.
TakahashiK., TanabeK., OhnukiM., NaritaM., IchisakaT., TomodaK., and YamanakaS. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872.
20.
UtikalJ., MaheraliN., KulalertW., and HochedlingerK. (2009). Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J. Cell Sci., 122, 3502–3510.
21.
van den BergD.L., SnoekT., MullinN.P., YatesA., BezstarostiK., DemmersJ., ChambersI., and PootR.A. (2010). An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell, 6, 369–381.
22.
WareC.B., WangL., MechamB.H., ShenL., NelsonA.M., BarM., LambaD.A., DauphinD.S., BuckinghamB., AskariB., LimR., TewariM., GartlerS.M., IssaJ.P., PavlidisP., DuanZ., and BlauC.A. (2009). Histone deacetylase inhibition elicits an evolutionarily conserved self-renewal program in embryonic stem cells. Cell Stem Cell, 4, 359–369.
23.
YuJ., VodyanikM.A., Smuga-OttoK., Antosiewicz-BourgetJ., FraneJ.L., TianS., NieJ., JonsdottirG.A., RuottiV., StewartR., and SlukvinI.I., and ThomsonJ.A. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318, 1917–1920.
24.
ZhangZ., GaoY., GordonA., WangZ.Z., QianZ., and WuW.S. (2011). Efficient generation of fully reprogrammed human iPS cells via polycistronic retroviral vector and a new cocktail of chemical compounds. PloS One, 6, e26592.
25.
ZhangZ., and WuW.S. (2013). Sodium butyrate promotes generation of Human iPS cells through induction of the miR302/367 cluster. Stem Cells Dev., 22, 2268–2277.
26.
ZhuS., LiW., ZhouH., WeiW., AmbasudhanR., LinT., KimJ., ZhangK., and DingS. (2010). Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell, 7, 651–655.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
