SUMOylation of Tr2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells

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The Tr2 orphan nuclear receptor can be SUMOylated, resulting in the replacement of coregulators recruited to the regulatory region of its endogenous target gene, Oct4. UnSUMOylated Tr2 activates Oct4, enhancing embryonal carcinoma-cell proliferation, and is localized to the promyelocytic leukemia (Pml) nuclear bodies. When its abundance is elevated, Tr2 is SUMOylated at Lys238 and seems to be released from the nuclear bodies to act as a repressor. SUMOylation of Tr2 induces an exchange of its coregulators: corepressor Rip140 replaces coactivator Pcaf, which switches Tr2 from an activator to a repressor. This involves dynamic partitioning of Tr2 into Pml-containing and Pml-free pools. These results support a model where SUMOylation-dependent partitioning and differential coregulator recruitment contribute to the maintenance of a homeostatic supply of activating, as opposed to repressive, Tr2, thus fine-tuning Oct4 expression and regulating stem-cell proliferation.

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Figure 1: Tr2 regulates Oct4 expression through DR1.
Figure 2: Tr2 SUMOylation by Ubc9 and Pias1.
Figure 3: Lys238 is essential for Tr2 SUMOylation.
Figure 4: Tr2 may partition in Pml nuclear bodies for SUMOylation.
Figure 5: SUMOylation of Tr2 switches its biological activity from activation to repression.
Figure 6: Tr2 SUMOylation in relationship to Oct4 expression and cell proliferation.

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This work was supported by US National Institutes of Health grants DK54733, DK60521, K02 DA13926 and DA11190 to L.-N.W. We also thank C.H. Lee and C. Chainpaisal for yeast screening and N.P. Tsai, F.C. Walosin and S.D. Persaud for technical support.

Author information

S.W.P. initiated the study of differential regulation of Oct4 by Tr2, designed and performed experiments and analyzed data. X.H. initiated and performed experiments on SUMOylation of Tr2 and constructed plasmids. P.G. conducted immunoprecipitations, mammalian two-hybrid assays and RNA interference experiments. Y.-P.L. conducted RT-PCR and ChIP assays. S.G.H. conducted immunofluorescence microscopy. L.-N.W. supervised the entire project and provided all the financial support.

Correspondence to Li-Na Wei.

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