MBD6 is a direct target of Oct4 and controls the stemness and differentiation of adipose tissue-derived stem cells
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Cellular and Molecular Life Sciences
RESEARCH ARTICLE
MBD6 is a direct target of Oct4 and controls the stemness and differentiation of adipose tissue-derived stem cells Jin Sun Jung • Min Ki Jee • Hyun Tae Cho • Jee In Choi Young Bin Im • Oh Hyun Kwon • Soo Kyung Kang
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Received: 18 May 2012 / Revised: 29 August 2012 / Accepted: 30 August 2012 / Published online: 30 September 2012 Ó Springer Basel AG 2012
Abstract Argonaute 2 (Ago2) is a pivotal regulator of cell fate in adult stem cells. Its expression is significantly downregulated in late passages of cells, concomitant with a prominent increase in Ago2 cytosolic localization in single cells. Nuclear localization of Ago2 is crucial for the survival, proliferation, and differentiation of hATSCs (human adipose tissue-derived stem cells), mediated by the specific binding of the regulatory regions of functional genes, which positively or negatively altered gene expression. Ago2 targets genes that control stemness, reactive oxygen species scavenging, and microRNA expression, all of which are crucial for hATSC survival and self-renewal. Ago2 promotes cell proliferation and self-renewal by activating the expression of octamer-binding transcription factor 4 (Oct4). We confirmed the direct regulation of Oct4 activity by Ago2, as indicated by the results of the ChIP analysis. Methyl-CpG-binding protein 6 (MBD6) was detected as an Oct4 regulatory gene. As predicted, knockdown of MBD6 expression attenuated cell proliferation and eventually induced cell death. We hypothesized that MBD6 functions downstream of Oct4 in the regulation of stemness-related genes, cell proliferation, self-renewal activity, and survival. MBD6 also promoted cell transdifferentiation into neural and endodermal b-cells while Jin Sun Jung and Min Ki Jee contributed equally to this work.
Electronic supplementary material The online version of this article (doi:10.1007/s00018-012-1157-4) contains supplementary material, which is available to authorized users. J. S. Jung M. K. Jee H. T. Cho J. I. Choi Y. B. Im O. H. Kwon S. K. Kang (&) Laboratory of Stem Cell Biology, Department of Biotechnology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea e-mail: [email protected]
significantly attenuating differentiation into the mesodermal lineage. We demonstrate that MBD6 is regulated by Ago2 via an interaction with Oct4, which alters selfrenewal and gene expression in hATSCs. MBD6 was promoted cell proliferation through a novel set of signal mediators that may influence differentiation by repressing MBD2 and MBD3, which are possibly recruited by germ cell nuclear factor (GCNF). Keywords Ago2 hATSC Methyl-CpG-binding protein 6 Oct4 Abbreviations Ago2 Argonaute2 BRCA2 Breast cancer type 2 susceptibility protein BrdU 5-bromo-20 -deoxyuridine CDK Cyclin-dependent kinases CFU Colony forming unit CM-Dil Chloromethyl-benzamidodialkylcarbocyanine DCAF-DA 10 , 70 -Dichlodihydrofluorescein diacetate FOXG1 Forkhead box protein G1 GFAP Glial fibrillary acidic
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