Role of Id1 in embryonic stem cell self-renewal and differentiation

Understanding the mechanism by which embryonic stem (ES) cells self-renew will be critical for the realization of their therapeutic potential. In this work, we show that the transcription factor Inhibitor of DNA-binding 1 (Id1) is required in mouse ES cells to maintain their normal self-renewal capacity and to block differentiation. Chronic or acute loss of Id1 leads to a down-regulation of Nanog, a critical regulator of self-renewal. We show that the loss of both Nanog and Id1 is required for the up-regulation of the transcription factor and mesendoderm marker Brachyury, an event that drives differentiation. Id1 is found to maintain Nanog expression by blocking the expression of Zeb1, a strong repressor of Nanog transcription. As Nanog can in turn up-regulate Id1 expression, this establishes a positive feedback loop capable of maintaining ES cell homeostasis. These results identify Id1 as an important factor in the maintenance of ES cell self-renewal and suggest a plausible mechanism for its control of lineage commitment.