Pluripotency of embryonic stem (ES) cells is maintained by transcription factors that form a highly interconnected protein interaction network surrounding the homeobox protein Nanog. Enforced expression of Nanog in mouse ES (mES) cells promotes self-renewal and alleviates their requirement for leukemia inhibitory factor (LIF). Understanding molecular mechanisms by which Nanog functions should illuminate fundamental properties of stem cells and the process of cellular reprogramming. Previously, we showed that Nanog forms multiple protein complexes in mES cells. Here, we demonstrate that Nanog dimerizes through its C-terminal domain rather than the homeodomain. Dimerization is required for interaction with other pluripotency network proteins. We also show that enforced expression of the Nanog dimer, but not the monomer, functionally replaces wild-type Nanog to sustain LIF-independent self-renewal of ES cells. Our results demonstrate that Nanog-Nanog homodimerization is a critical aspect of its function promoting stem cell pluripotency.
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