Reversine increases the plasticity of lineage-committed cells toward neuroectodermal lineage.
Functional dedifferentiation of lineage-committed cells toward pluripotency may have a great potential in regenerative medicine. Reversine has been shown to induce dedifferentiation of multiple terminally differentiated mesodermal origin cells, which are capable of being directed to differentiate into other cell types within mesodermal lineages. However, the possibilities of these cells to give rise to other lineages have not been examined. Here we show that large scale gene expression profiling of reversine-treated C2C12 myoblasts identifies a subset of up-regulated genes involved in specification of neuroectodermal as well as mesodermal lineages. Reversine treatment leads to up-regulation of priming genes of neuroectodermal lineages, such as Ngn2, Nts, Irx3, Pax7, Hes1, and Hes6, through active histone modifications in the promoter regions of these genes. Additionally, reversine increases the expression of markers for other cell types of mesodermal lineages, Ogn and apoE, via inducing active histone modifications, while down-regulating the myogenic basic helix-loop-helix factor, MyoD, via repressive histone modifications. Consistent with up-regulation of these genes, reversine-treated C2C12 myoblasts redifferentiate into neural as well as mesodermal lineages, under appropriate stimuli. Taken together, these results indicate that reversine induces a multipotency of C2C12 myoblasts via inducing a specific combination of active histone modifications. Collectively, our findings provide a mechanistic rationale for the application of reversine to dedifferentiation of somatic cells.
Lee
Eun Kyung
EK
Department of Biochemistry and Molecular Biology, College of Pharmacy, Suwon 440-746.
Bae
Gyu-Un
GU
Samsung Biomedical Research Institute, Sungkyunkwan University, Suwon 440-746.
You
Jueng Soo
JS
Department of Biochemistry and Molecular Biology, College of Pharmacy, Suwon 440-746.
Lee
Jae Cheol
JC
Department of Biochemistry and Molecular Biology, College of Pharmacy, Suwon 440-746.
Jeon
Yae Jee
YJ
Department of Biochemistry and Molecular Biology, College of Pharmacy, Suwon 440-746.
Park
Jong Woo
JW
Department of Biochemistry and Molecular Biology, College of Pharmacy, Suwon 440-746.
Park
Jae Hyun
JH
Department of Biochemistry and Molecular Biology, College of Pharmacy, Suwon 440-746.
Ahn
Seong Hoon
SH
Division of Molecular and Life Sciences, Hanyang University, Ansan 426-791.
Kim
Yong Kee
YK
College of Medicine, Kwandong University, Gangneung 210-701.
Choi
Wahn Soo
WS
College of Medicine, Konkuk University, Chungju 380-701.
Kang
Jong-Sun
JS
Samsung Biomedical Research Institute, Sungkyunkwan University, Suwon 440-746.
Han
Gyoonhee
G
Department of Biotechnology, Yonsei University, Seoul 120-749, Korea.
Han
Jeung-Whan
JW
Department of Biochemistry and Molecular Biology, College of Pharmacy, Suwon 440-746. Electronic address: jhhan551@skku.edu.
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage; D017931:DNA Primers; D020869:Gene Expression Profiling; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D017931:DNA Primers; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; C484369:2-(4-morpholinoanilino)-6-cyclohexylaminopurine