Roles for myc in self-renewal of pluripotent stem cells

Abstract

Myc is a critical factor for embryonic stem cell maintenance. It also enhances the reprogramming of fibroblasts by effecting widespread changes in gene expression, effectively silencing the somatic cell gene expression program. Significant effort has been placed into identifying myc targets in embryonic stem cells as a step to define mechanisms of myc action. However, despite this, how myc regulates self-renewal and pluripotency remains unknown. To fill this gap, target genes and interacting proteins of c-myc in embryonic stem cells have been identified on a global scale. Key interacting proteins include epigenetic regulators Smarca4 and LSD1, which are important regulators of gene activation and repression in embryonic stem cells. Target genes of particular interest include the miR-17-92 cluster, through which myc acts to establish the cell cycle structure that is crucial for the maintenance of self-renewal. A second is the primitive endoderm specification factor Gata6. Myc binds to the promoter region of Gata6 in pluripotent cells and directly represses its transcription. In the absence of c- and N-myc, pluripotent cells differentiate to endoderm, concomitant with an increase in Gata6 transcription. The demonstration that myc represses Gata6 is a step toward defining mechanisms of pluripotent stem cell maintenance by myc. This mechanism of repression of lineage specific differentiation by myc was delineated by generating induced pluripotent cells, and inactivating c-myc and N-myc simultaneously. These experiments demonstrate that c- or N-myc is an absolute requirement for maintenance of the embryonic stem cell state, and one mechanism of sustaining self-renewal is repression of primitive endoderm differentiation.