A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages

• Published in: Nature cell biology Vol. 15; no. 6; pp. 579 - 590
• Main Authors: Radzisheuskaya, Aliaksandra, Le Bin Chia, Gloryn, dos Santos, Rodrigo L., Theunissen, Thorold W., Castro, L. Filipe C., Nichols, Jennifer, Silva, José C. R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2013; Nature Publishing Group
• Subjects: 631/136/2444; 631/136/532/2064/2117; 631/45/612/822; Animals; Biology; Cancer Research; Cell Biology; Cell Differentiation; Cell Lineage; Cells, Cultured; Developmental Biology; Embryonic stem cells; Embryonic Stem Cells - metabolism; Gene expression; Gene Expression Profiling; Gene Knockout Techniques; Genetic aspects; Homeodomain Proteins - genetics; Induced Pluripotent Stem Cells - metabolism; Kinases; Life Sciences; Mice; Nanog Homeobox Protein; Neural Stem Cells; Neurosciences; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Physiological aspects; Stem Cells; Tennis; United States; United Kingdom > UK; Portugal
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2742

Oct4 is considered a master transcription factor for pluripotent cell self-renewal, but its biology remains poorly understood. Here, we investigated the role of Oct4 using the process of induced pluripotency. We found that a defined embryonic stem cell (ESC) level of Oct4 is required for pluripotency entry. However, once pluripotency is established, the Oct4 level can be decreased up to sevenfold without loss of self-renewal. Unexpectedly, cells constitutively expressing Oct4 at an ESC level robustly differentiated into all embryonic lineages and germline. In contrast, cells with low Oct4 levels were deficient in differentiation, exhibiting expression of naive pluripotency genes in the absence of pluripotency culture requisites. The restoration of Oct4 expression to an ESC level rescued the ability of these to restrict naive pluripotent gene expression and to differentiate. In conclusion, a defined Oct4 level controls the establishment of naive pluripotency as well as commitment to all embryonic lineages.
Using embryonic stem cells (ESCs) expressing controlled levels of Oct4 (a master transcription factor for pluripotency and reprogramming), Silva and colleagues show that although ESC levels of Oct4 are needed for pluripotency entry, Oct4 levels can decrease once pluripotency is established, without affecting self-renewal. However, ESC levels of Oct4 are required for differentiation to all lineages, as cells with low levels of Oct4 during differentiation remain in a naïve pluripotent state.