Polycomb Proteins Pave the Way for Proper Stem Cell Differentiation


Embryonic stem cells have the ability to differentiate into one of the more than 200 cell types. Differentiation requires a strictly regulated program of gene expression that turns certain genes on at specific times and shuts other genes off. Loss of this regulatory circuit prevents stem cells from properly differentiating into adult cell types, and an inability to differentiate has also been linked to the onset of cancer.

Researchers at the BRIC, University of Copenhagen have identified a crucial role of the molecule Fbx110 in embryonic stem cell differentiation. Kristian Helin from the BRIC said, “Our new results show that this molecule is required for he function of one of the most important molecular switches that constantly regulated the activity of our genes. If Fbx110 is not present in embryonic stem cells, the cells cannot differentiate properly and this can lead to developmental defects.”

What is the function of Fbx110? Fbx110 recruits members of the “Polycomb” gene family to DNA. Polycomb proteins, in particular PRC1 & 2, are known to modulate the structure of chromatin, even though they do not bind DNA. Fbx110,, however binds DNA, but it also binds PRC1 . Therefore, Fbx110 seems to serve as an adapter that recruits Polycomb proteins to DNA.

Polycomb proteins bound to nucleosomes
Polycomb proteins bound to nucleosomes

Postdoctoral fellow Xudong Wu, who led the experimental part of this investigation, said, “Our results show that Fbx110 is essential for recruiting PRC1 to genes that are to be silenced in embryonic stem cells. Fbx110 binds directly to DNA and to PRC1, and this way it serves to bring PRC1 to specific genes. When PRC1 is bound to DNA it can modify the DNA associated proteins, which lead to silencing of the gene to which it binds.”

Timing of gene activity is crucial during development and must be maintained throughout the lifespan of any cell. Particular genes are active at a certain times and inactive at other times, and PRC1 seems to be part of the reason for this coordination of gene activity. PRC1 is dynamically recruited to and dissociates from genes according to the needs of the organism.

When cancer arises, this tight regulation of gene activity is often lost and the cells are locked in an inchoateĀ state. This loss of terminal differentiation causes increases cell proliferation and the accumulation of other mutations that allow the cancer cells to undergo continuous self-renewal through endless cell divisions. Such an ability is denied to mature cells because of their tightly controlled programs of gene expression.

Wu added, “Given the emerging relationship between cancer and stem cells, our findings may implicate that an aberrant activity of Fbx110 can disturb PRC function and promote a lack of differentiation in our cells. This makes it worth studying whether blocking the function of Fbx110 could be a strategy for tumor therapy.”

In collaboration with a biotech company called EpiTherapeutics, the BRIC researchers want to develop Fbx110 inhibitors asĀ potential novel therapies for cancer.

The Role of Astrocytes in Lou Gehring’s Disease


A study from Columbia University and Harvard University has uncovered a complex interplay between neurons and support cells known as astrocytes that contributes to the pathology of ALS. Such an intricate interplay complicates regenerative therapies for this disease.

In the spinal cord, a group of neurons called motor neurons extend their axons to skeletal muscles and provide the neural signals for the muscles to contract, which allows movement. Motor neurons also have associated support cells known as glial cells, and a specific group of glial cells known as astrocytes associate with motor neurons in the spinal cord.

Astrocytes are star-shaped cells that surround neurons in the brain and spinal cord, and they outnumber neurons 50:1. Astrocytes are very active in the central nervous system, and serve to maintain, support, and repair the nervous tissue that they serve, and are responsible, in large part, for the plasticity of the nervous system.

astrocytes1 (1)

Motor neurons die off during the course of ALS, which leads to paralysis and death within two to fives years of diagnosis. ALS also affects neurons in the brain and it completely robs the individual of the ability to initiate movement or even breathe. There is, at present, no cure and no life-prolonging treatment for ALS.

Data from the ALS Association group suggests that astrocytes in ALS patients go from supporting neurons to strangling them. According to Lucie Bruijn, the chief scientist at the ALS Association in Washington D.C.,, these results seem to “strengthen the case that astrocytes are central to the ALS disease process.” She continued: “Furthermore, the results are based on an exciting new disease model system, one that will allow us to test important hypotheses and search for new therapeutic targets.”

In a cell culture system of ALS, in which neurons derived from embryonic cells were co-cultured with normal and ALS astrocytes, Bruijn’s team found that gene expression patterns in those neurons associated with ALS astrocytes were abnormal. In this experiment, neurons derived from embryonic stem cells with co-cultured with normal and ALS affected astrocytes. In a time course experiment in which gene expression profiles were analyzed from the neurons after specific amounts of time, the gene expression patterns from the normal astrocytes co-cultured with neurons were compared with those of the ALS-affected astrocytes co-cultured with neurons. From these experiments, it became clear that the ALS-affected astrocytes did not communicate properly with the nearby neurons.

Even though neurons communicated with each other by means of the release of neurotransmitters, astrocytes and other glial cells also communicate with each other by means of the release of various molecules. This astrocyte-neuron communication maintains healthy neuron function. However, in the case of ALS, the neuron-astrocyte communication is “profoundly disrupted” and is disruption is not neuron dependent, since in this experiment, the neurons were normal. Without proper communication with their astrocytes, motor neurons the spinal cords of ALS patients are not able to function properly.

According to Bruijn, “This study points out several potential points for treatment intervention.” The protection of motor neurons is the goal, since the astrocytes seem to be doing little to protect and support the neurons and also might be hurting them.

An added bonus to this study is that when spinal cords from mice with a disease that shows some similarities to ALS have their gene expression profiles compared to these gene expression profiles observed in the cultured neurons, the results are remarkably similar. This shows that culture system does recapitulate what goes on in the spinal cord.

The next step is to show that the molecular abnormalities discovered in this system mimics those that occur in human disease. This publication utilized mouse cells, and the human disease, while similar, is not exactly the same.