Work published today by the Hendrich lab solves a major conundrum in the chromatin field: how can a single chromatin remodelling complex activate expression at some genes while repressing expression at others?
While the vast majority of cells in the body contain exactly the same set of genetic instructions, they nevertheless develop very different characteristics. Cells in the heart, the brain, the liver, or the skin are all genetically identical but adopt different shapes and serve very different functions. The cell’s instruction manual is found within the genetic code on the DNA, and the characteristics of a given cell are chosen based on the genes that are turned on or turned off in that cell.
The team, led by Dr. Brian Hendrich, used mouse embryonic stem cells to study a cluster of proteins known to be important for controlling gene expression called “The NuRD Complex.” While previous work indicated that NuRD simply turns genes off, the researchers found that NuRD’s role in controlling gene expression is actually more subtle, fine tuning the activity of genes rather than acting as an on – off switch.
The group found that NuRD directly controls how sections of DNA important for controlling gene expression are packaged within the cell. Changing the DNA packaging affects the access of other regulatory proteins to the genes within the DNA. For example, NuRD controls the access of RNA polymerase, the protein complex which “reads” the genes within the DNA. Importantly, this control of protein access by NuRD does not cause all-or-none changes in gene expression as was previously thought, but rather acts to finely regulate genetic activity.
“NuRD acts as something like a gatekeeper, deciding which proteins can access the DNA and therefore which genes are able to respond when a stem cell needs to differentiate into one cell type or another“ explained Nicola Reynolds, one of the lead authors on the study. “Stem cells are particularly sensitive to this since these cells can differentiate into many different cell types. These cells use NuRD’s ability to finely tune gene expression in order to make the right decisions at the right time.”
Dr Brian Hendrich, who led the study, said “This work is important for understanding fundamental biological questions about how stem cells decide which cells to become, but will also guide future work into human diseases, such as cancer, where the cellular decision making processes are disrupted.”
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The support of the Wellcome, Medical Research Council, European Molecular Biology Laboratory and the Biotechnology and Biological Sciences Research Council has been invaluable in facilitating this research, and is gratefully acknowledged by Brian and the team.
Reference: Bornelöv, Susanne et al. The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression.
Molecular Cell DOI: https://doi.org/10.1016/j.molcel.2018.06.003