COPENHAGEN, Denmark, August 12, 2013 – The protein CHD5 has been proposed as a tumor suppressor, preventing healthy cells from developing into cancer cells.
But the part played by the protein in healthy tissue, and whether this role is important for its ability to counter tumor growth, has remained largely uncharted.
Now, researchers at Karolinska Institutet, working with colleagues at Trinity College in Dublin and BRIC in Copenhagen, have revealed its function in normal nervous system development and as a tumor suppressor.
The study shows that when stem cells approach the final phase of their specialization as neurons, CHD5 begins to be expressed at high levels. CHD5 can reshape the chromatin, in which DNA is packed around proteins, and in so doing either facilitate or obstruct the expression of genes.
Ulrika Nyman, postdoc researcher in Dr. Johan Holmberg’s research group and co-author, said that they switched off CHD5 in the stem cells of mice embryos during the period in which the brain develops and the majority of neurons are formed.
They found that without CHD5, a stem cell is unable to silence the expression of a number of stem cell genes and genes that are actually to be expressed in muscle, blood or intestinal cells.
There was also observed an inability in the stem cell to switch on the expression of genes necessary for it to mature into a neuron, leaving it trapped in a stage between stem cell and neuron.
The gene that codes for CHD5 is found on part of chromosome 1 (1p36) that is often lost in tumor cells in a number of cancers, particularly neuroblastoma, a disease that strikes mainly children and is thought to arise during the development of the peripheral nervous system.
Neuroblastoma lacking this section of chromosome and thus also CHD5 are often more aggressive and more rapidly fatal.
Treatment with retinoic acid can make immature nerve cells and some neuroblastoma cells mature into specialized nerve cells, but when the researchers prevented neuroblastoma cells from upregulating CHD5, the tumors no longer responded to retinoic acid treatment.
“In the absence of CHD5, neural tumor cells cannot mature into harmless neurons, but continue to divide, making the tumor more malignant and much harder to treat,” said Holmberg. “We now hope to be able to restore the ability to upregulate CHD5 in aggressive tumor cells and make them mature into harmless nerve cells.”
Citation: “CHD5 Is Required for Neurogenesis and Has a Dual Role in Facilitating Gene Expression and Polycomb Gene Repression”; Chris M. Egan et al.; Developmental Cell, 2013; 26 (3): 223 DOI: 10.1016/j.devcel.2013.07.008
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Contact: Johan Holmberg, email@example.com