Rett mutations may disrupt DNA-packaging proteins in nerve cells
Mouse study found histone changes varied by nerve cell type and mutation
Written by |
In mouse models of Rett syndrome, disease-related changes in the MeCP2 protein were linked to widespread disruptions in histones, proteins that help package DNA and regulate gene activity within cells.
That’s according to the study, “Spatially resolved mapping of histones reveals selective neuronal response in Rett syndrome,” published in The FEBS Journal.
The results suggest that Rett-related effects on nerve cells vary depending on the specific type of nerve cell and the specific type of Rett-causing mutation, which researchers said may have implications for future research and, eventually, efforts to tailor treatments.
Researchers studied how MeCP2 changes affect histones
Rett syndrome is a rare genetic disorder caused by mutations in the MECP2 gene, which provides instructions to make a protein of the same name. Rett-causing mutations disrupt the function of the MeCP2 protein, and some can reduce its levels. These changes cause neurological problems that ultimately give rise to Rett symptoms, though the specific biochemical mechanisms of how MeCP2 protein dysfunction alters the activity of nerve cells in the brain are not fully understood.
MeCP2 is known to help cells regulate chromatin — the complex of DNA and proteins that forms the structure of chromosomes. In this study, researchers in Germany and Italy wanted to know if MeCP2 also affects proteins called histones, which act like spools that long strands of DNA wrap around. This wrapping plays key roles in regulating gene activity: inactive genes are tightly wrapped so they can be packed away, while active genes are loosely wrapped for easy access.
Cells produce several different types of histones, each with unique functions, similar to how a seamstress might keep different-colored threads on different-sized spools. Here, the scientists used a detailed set of molecular tests to characterize the histone makeup of nerve cells with or without MeCP2 protein, including different histone forms and chemical modifications.
For their experiments, the researchers used mice engineered to lack MeCP2 protein, and they specifically looked at nerve cells in two brain regions: the hippocampus, which is crucial for memory, and the cerebellum, which helps control coordination.
Histone changes varied by nerve cell type
The investigators found that MeCP2-deficient neurons showed marked changes in their histone makeup — and notably, different types of nerve cells had different patterns of histone changes. This underscores the importance of looking at how the disease affects each type of nerve cell, rather than trying to look at the disease’s impact in the brain as a whole.
“Across neuronal populations, we observe significant variation in histone composition, suggesting localized alteration of epigenetic architecture that reflects a distinct response to functional loss of [MeCP2 protein],” the researchers wrote. In this context, epigenetics refers to changes in how DNA and histone proteins are packaged and regulated, which can affect gene activity without changing the DNA code itself.
The team then conducted similar tests using mice that produced a disease-causing mutant version of MeCP2, known to cause different chromatin changes than a complete lack of MeCP2. Mice with that mutation, called Y120D, also had histone changes, but they were more subtle and the patterns were different than in mice completely lacking MeCP2.
For instance, in mice with the Y120D mutation, overall acetylation of two histone types, H3 and H4, was largely unchanged in the dentate gyrus, a region of the hippocampus. However, overall acetylation showed a subtle increase in another hippocampal region and a decrease in the cerebellum.
Overall, the researchers said these differences reinforce the potential importance of applying personalized disease management strategies tailored to the specific Rett-causing mutation involved. They called for further studies aimed at understanding exactly how different Rett-causing mutations affect histone architecture, and the broader consequences for nerve cells’ health and development.
“Future efforts should aim to map these local effects across distinct chromatin compartments and neuronal populations, and to chart their progression over the disease course,” they added.
