How Pluripotent Stem Cells Stay Themselves

Embryonic stem cells (ESCs) have an uncanny ability to perpetually divide in culture and differentiate into any cell type found in the adult body. The internal switches inside ESCs that keep them pluripotent or drive them to differentiate are incompletely understood at this. However new work from the Carnegie Institution for Science has opened a new doorway into this event.

Yixian Zheng and his research team has focused on the process by which ESCs stay in their pluripotent state. There are three protein networks within the cell that direct the self-renewal and differentiation aspects of cell behavior. These networks consist of 1) the pluripotent core, which includes the protein called Oct4 and its many co-workers; 2) the Myc-Arf network, which directs cell proliferation, and 3) the PRC2 or polycomb proteins, which repress genes necessary for differentiation. How these networks are integrated remains quite unclear. Zhen and his group have found a protein that seems to link all three of these networks together.

A protein called Utf1 seems to act as the cord that ties all three of these networks together. First, Utf1 limits the loading of PRC2 on the DNA and it also prevents PRC2 from modifying chromatin so that the DNA assumes a very tight, compact structure that prevents gene expression. Thus, Utf1 keeps the DNA somewhat poised and ready for gene expression, should the proper conditions come about that favor differentiation. Secondly,. for those genes that are not completely shut off by PRC2, Utf1 works through a protein complex called the DCP1a complex to degrade these mRNAs made these incompletely repressed genes. Finally, Utf1 downregulates the My-Afr feed pathway. The Myc and Arf work together to curtail cell proliferation, but the inhibition of this pathway ensures that the cell continues to divide properly.

According to Zheng, “We are slowly but surely growing to understand the physiology of embryonic stem cells. It is crucial that we continue to carrying out [sic] basic research on how these cells function.”

Zheng is a Howard Hughes Medical Institute Researcher at the National Institutes of Health and in the Department of Embryology at the Carnegie Institute for Science in Baltimore, Maryland.

This work was published in the journal Cell under the title, “Regulation of pluripotency and self-renewal of ESCs through epigenetic-threshold modulation and mRNA pruning.” Cell 2012 3:576.