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September 2011

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Understanding how embryonic stem cells work

By Robin Arnette
September 2011

Raja Jothi, Ph.D.

Jothi is head of the Systems Biology Group in the NIEHS Biostatistics Branch. (Photo courtesy of Steve McCaw)

In the July 24 issue of Nature Cell Biology, NIEHS researcher Raja Jothi, Ph.D., (http://www.niehs.nih.gov/research/atniehs/labs/escbl/pi/systemsbiology/index.cfm)published a paper(http://www.ncbi.nlm.nih.gov/pubmed/21785422) Exit NIEHS that explains how two seemingly opposing mechanisms in embryonic stem (ES) cells actually work together. Jothi said a few papers in the literature suggested that this unique cellular collaboration occurs on a gene-by-gene basis, but his findings were the first to demonstrate that it happens quite frequently on a genome-wide scale.

In a collaborative effort, Jothi and his colleagues in the lab led by Gerald Crabtree, M.D., at the Howard Hughes Medical Institute (HHMI) and Stanford University School of Medicine, wanted to understand how ES cells function given their potential for curing disease. ES cells have the ability to become any cell in the adult body. This capability, known as pluripotency, offers scientists the possibility of treating a host of conditions, such as Parkinson's disease, burns, diabetes, spinal cord injury, arthritis, and amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease.

Using data sets generated at the NIEHS sequencing facility, Jothi, a co-senior author on the paper along with Crabtree, performed the genome-scale analysis. Lena Ho, Ph.D., a graduate student at the time in Crabtree's lab, carried out the experiments. Jothi also shared co-first authorship with Ho on the article.

The players in pluripotency

Jothi provided a little background for the research by saying that the chromatin remodeling complex, esBAF, and the LIF/STAT3 signaling pathway are two critical components required to maintain mouse ES cells in the undifferentiated pluripotent state. esBAF is a multiprotein complex responsible for unwinding tightly packaged DNA so that other proteins can gain access to bind DNA and turn genes on or off in a context-dependent manner.

Jothi said the leukemia inhibitory factor (LIF) pathway, mediated by its downstream DNA binding transcription factor STAT3, is absolutely essential for pluripotency, because it inhibits mouse ES cells from differentiating into mesoderm and endoderm, two of the three primary germ layers of an embryo that is the source of many bodily tissues that include lung, liver, heart and blood cells.

He cited the team's earlier study(http://www.ncbi.nlm.nih.gov/pubmed/19279218) Exit NIEHS showing esBAF's colocalization with STAT3 promotes pluripotency, but these latest findings demonstrated that it is primarily achieved by esBAF both working against and in concert with polycomb, a third player in this molecular drama. Polycomb is repressive machinery that silences developmental and differentiation genes when bound to DNA.

“We wanted to show that esBAF facilitates binding of STAT3 by opposing polycomb and, during our analysis, we started seeing it,” Jothi said. “Traditionally, trithorax-group proteins, of which esBAF is a member, and polycomb play antagonistic roles in development but, unexpectedly, we also found that there are instances, like at all four Hox gene clusters, where these two can work together to effectively silence Hox genes and prevent premature differentiation.”

Implications for stem cell research

Jothi said that they were a little skeptical when they found that esBAF can facilitate polycomb action, given the traditional view of their antagonistic roles. Fortunately, he and his colleagues were able to demonstrate how these two act both antagonistically and synergistically with the common goal of maintaining pluripotency in ES cells.

Crabtree agreed that the results were very relevant to the field. He said, “The study nicely illustrates the power of modern genome-wide analysis to reverse old biases. All biochemistry and developmental textbooks have polycomb and chromatin remodeling machinery opposing one another. Yet, when one analyzes the entire genome, it is clear that opposition is only a small part of the picture.”

Another stem cell expert, Guang Hu, Ph.D., head of the NIEHS Laboratory of Molecular Carcinogenesis Stem Cell Biology Group(http://www.niehs.nih.gov/research/atniehs/labs/lmc/stemcell/index.cfm), believes the paper greatly pushes ES research forward. He added, “This work greatly improved our understanding of the transcriptional control of self-renewal and pluripotency. It may help us understand reprogramming and find better ways to generate pluripotent cells in the future.”

Citation: Ho L, Miller EL, Ronan JL, Ho WQ, Jothi R, Crabtree GR. (http://www.ncbi.nlm.nih.gov/pubmed/21785422) Exit NIEHS2011. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nat Cell Biol 13(8):903-913.

Antagonism and Synergism Between esBAF and PRC2 promotes pluripotency

In this model, the chromatin remodeling complex esBAF acts as a general facilitator by providing DNA access in a context-dependent manner. At genes regulated by LIF/STAT3, esBAF facilitates STAT3 binding by antagonizing repressive polycomb action and allowing LIF/STAT3 to activate pluripotent genes. At Hox gene clusters, esBAF facilitates polycomb (PRC2) binding to silence Hox genes. In the absence of both esBAF and PRC2, LIF/STAT3 is able to bind and keep the ES cells in a pluripotent state.
(Image courtesy of Raja Jothi)

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