Findings strengthen the concept that the roles of this protein — MeCP2 — are primarily focused on nucleosomes instead of other DNA structures.
A specific protein plays a vital role in the development of the brain. It’s a key regulator of gene expression and is found in high levels within neurons. When this protein malfunctions, it can lead to Rett syndrome, a neurological condition that may cause severe cognitive, motor, and communication difficulties, particularly in young girls.
However, our understanding of how this crucial protein performs its critical tasks at the molecular level remains limited. “For decades, researchers have been examining this protein without reaching a clear agreement on its functions, specific genomic binding sites, or its overall roles,” explains Shixin Liu from Rockefeller. A recent study from Liu’s lab offers new insights into how the protein, MeCP2, engages with DNA and chromatin.
The research, published in Nature Structural & Molecular Biology, sheds light on this important regulator and has the potential to pave the way for new treatments for Rett syndrome.
A single-molecule approach
MeCP2 is a puzzling protein. It has been linked to the regulation of numerous genes and is believed to play a crucial role in neurodevelopment, but its effects on the genome are challenging to define. Insufficient levels of normal MeCP2 result in Rett syndrome, while excessive amounts can lead to another serious neurological condition known as MeCP2 duplication syndrome.
Liu and his team used their expertise in observing and manipulating single molecules to gain a better understanding of how MeCP2 interacts with DNA. They attached a single strand of DNA between tiny plastic beads, each held in place with a laser, and then exposed the DNA to fluorescently labeled MeCP2 proteins. This arrangement allowed them to closely observe the dynamic behavior of this enigmatic protein.
Traditionally, MeCP2 is thought to mainly operate on DNA modified with methylated cytosines, yet there has been a lack of a convincing explanation for this selectivity, as the protein can bind both methylated and unmethylated DNA. The study showed that MeCP2 moves along DNA, but its movement is significantly slower on methylated DNA compared to unmethylated DNA. Moreover, these distinct movement patterns enable MeCP2 to more efficiently attract another regulatory protein to sites of methylated DNA, potentially guiding MeCP2’s gene regulatory functions to specific genome locations. “We discovered that MeCP2 slides quicker on unmethylated DNA, and this variance in speed may clarify how the protein differentiates between the two forms,” said Gabriella Chua, a graduate fellow in Liu’s lab and the first author of the study.
“This is something we could only have discovered through a single-molecule technique.”
Liu and Chua also observed that the protein exhibits a strong preference for binding to nucleosomes—protein structures that encase our genetic material—over naked DNA. This interaction stabilizes nucleosomes and could potentially suppress gene transcription, providing insights into how MeCP2 regulates gene expression.
A fresh perspective on nucleosomes
The finding that a primary regulator of gene expression frequently interacts with this tightly coiled form of DNA supports the growing belief that nucleosomes serve a purpose beyond merely being passive “storage spools” for DNA. It suggests that scientists should view MeCP2’s functions primarily in the context of nucleosomes.
“Our data is among the clearest examples of this phenomenon available,” states Liu. “It’s evident that MeCP2 has a preference for nucleosome binding.” In this context, MeCP2 acts as a chromatin-binding protein, which contrasts with the traditional perspective that primarily considers it a methyl-DNA-binding protein. The study has also pinpointed the region of the protein responsible for its ability to bind nucleosomes.
“Naked DNA is relatively rare — nucleosomes are widespread throughout our genomes,” remarks Chua. “Several recent studies have demonstrated that nucleosomes are not merely inactive barriers to transcription, but are dynamic hotspots essential for gene regulation.” A particularly notable illustration of this nucleosome functionality is found in how MeCP2 interacts with them.
In future research, the team intends to broaden their investigation beyond the current laboratory settings to examine MeCP2 in living organisms, where the interactions between the protein and nucleosome are likely to be more intricate. They also aim to utilize the techniques outlined in this study to delve deeper into the various MeCP2 mutations associated with conditions like Rett syndrome. The goal is to achieve a more comprehensive understanding of this vital protein, which could one day lead to effective treatments. “Currently, there is no remedy for Rett syndrome, but the research community focused on this condition is motivated and energized. Many colleagues found our results intriguing when we shared them,” comments Chua. “Our findings emphasize how foundational research can assist the clinical community in gaining a better grasp of a disease.”
