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GEN News Highlights : Mar 3, 2009

Protein Complex that Determines Stem Cell Pluripotency Found

PNAS paper says esBAF controls the expression of the four pluripotent factors.

Scientists at the Stanford University School of Medicine have identified a protein complex that determines whether embryonic stem cells retain their pluripotency or begin to mature and specialize.

Embryonic-stem-cell BAF (esBAF) seems to work by adjusting the expression levels of c-Myc, Klf4, Oct4, and Sox2, which help change adult stem cells into an embryonic-like state. They suggest that EsBAF works by affecting the way DNA is packaged within the cells in chromatin.

“We’ve identified a specific mechanism to maintain pluripotency that involves large-scale, genome-wide chromatin remodeling,” explains Gerald Crabtree, M.D., professor of pathology and developmental biology at the medical school. “The results are rather spectacular. They show clearly that the complex binds to and works in near-perfect concert with these four famous pluripotent factors. They are part of the same developmental program.” 

They also discovered that esBAF can both activate and inactivate the expression of the genes and posit that perhaps this refining function is what keeps embryonic stem cells in a state between self-renewal and differentiation.

These results stemmed from an investigation into the function of BAF after researchers had found that it was important in regulating how a cell’s genetic material is wrapped around histones. One way of controlling how and when a gene is made into a protein involves increasing or restricting its accessibility to transcription factors, and BAF is one of many so-called chromatin remodeling complexes that regulate this process in mammals.

The researchers found that the protein components of BAF vary according to the cell type in which they are found. They thus began to look more closely at how BAF functions in embryonic stem cells, which when they discovered esBAF.
The researchers are now investigating whether they can manipulate the subunits of the esBAF complex to make fibroblasts pluripotent and attempting to determine whether small molecules or chemicals modulate the complex’ function.

Two articles describing the work appeared in the online edition of the Proceedings of the National Academy of Sciences on  March 2.