Key Role Discovered for Enzyme in Preserving Essence of Stem Cells

A highly conserved yet unique acetyltransferase has now been shown to be essential in maintaining the self-renewal and pluripotent capacities of embryonic stem cells.

A team of scientists, primarily from the University of Michigan Medical School (Ann Arbor, MI, USA), have discovered that Mof, the only histone acetyltransferase known to be important in the functioning of non-differentiated embryonic stem cells (ESCs), is involved in regulating the core transcription mechanism in those cells by epigenetically marking chromatin to keep parts of the genome readily accessible. In ESCs, many areas of DNA are kept open for access, probably because they also need to produce many proteins that prevent differentiation. Once an ESC starts to differentiate, parts of the DNA close up and are no longer as accessible. Many scientific teams have studied this “selective silencing” and the factors that cause ESCs to start specializing by reading only certain genes. But few have looked at the crucial but little understood factors that facilitate broad-range DNA transcription to preserve “stem-ness”.

“If you think about stem cell biology, the self-renewal is one aspect that makes stem cells unique and powerful, and the differentiation is another,” says lead scientist Yali Dou, PhD and associate professor of pathology and biological chemistry. “People have looked a lot at differentiation to make cells useful for therapy in the future – but the stem cell itself is actually pretty fascinating.” Prof. Dou and her team have also reported on the protein WDR5 that places chromatin tags important during transcription, but Mof appears to control the process that actually allows cells to determine which genes to transcribe. “Mof marks the areas that need to stay open and maintains the potential to become anything,” Prof. Dou explains. The findings of the current extensive study, published on August 3, 2012, in the journal Cell Stem Cell, also include that ESC Mof-deletion mutants lose characteristic morphology, alkaline phosphatase (AP) staining, and differentiation potential. Furthermore, these mutants have aberrant expression of the core transcription factors Nanog, Oct4, and Sox2.

The new findings may also have particular importance for work on induced pluripotent stem cells (IPSCs), stem cells made from “adult” tissue. IPSC research holds promise for disease treatment as it could allow patients to be treated with stem cells made from their own tissue. But the current way of making IPSCs from tissue involves a process that uses a cancer-causing gene, a step that might give doctors and patients pause. Prof. Dou says that further work on Mof might make it possible to stop using this potentially harmful approach.

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