Rett syndrome, a rare neurological disorder that results in the impairment of daily activities like speaking, walking, and eating, might be linked to problems with the formation of DNA-filled droplets that control gene expression.
Similar to drops of oil in water, droplets form throughout cells, the purpose of which is to compartmentalize molecules for specialized purposes. In a person’s DNA profile, droplets filled with DNA or heterochromatin are responsible for keeping some genes inaccessible. Mutations in the MECP2 gene, which encodes the protein necessary for nerve cells to function normally, have been linked to autism, and according to a new study, these mutations may disrupt the formation of aforementioned droplets, which may contribute to Rett syndrome.
According to Rudolf Jaenisch, the co-lead investigator of the study and a professor of biology at the Massachusetts Institute of Technology and the Whitehead Institute in Cambridge, Massachusetts, MECP2 protein sometimes acts as the bridge between DNA and the proteins that reduce gene expression, but this protein is also linked to gene activation.
This protein’s newly discovered role in droplet formation, which is also called phase transition, might be key in explaining its contradicting effects.
Jaenisch and his colleagues wanted to understand how the MECP2 structure affects droplet formation, and so they conducted a study by engineering mice that carry a fluorescent tag on MECP2 protein and using a dye that binds to heterochromatin. Through a microscope, the researchers saw that both MECP2 and heterochromatin had collected in the same spots. They repeated the experiment using mouse embryonic stem cells, and the results were similar.
Richard Young, a biology professor at the Massachusetts Institute of Technology and the Whitehead Institute and the study’s co-lead investigator, claims that the results of the experiment are consistent with what is known about MECP2 and how it interacts with DNA, but it is being seen for the first time in the context of a reconstituted liquid droplet.
He adds that a number of nuclear regulatory processes are now understood to take place in phase transitions, and that droplet assays have also provided key insights into how these molecules behave.
The Connection to Rett Syndrome
Associated with constant repetitive hand movements, Rett syndrome is classified as an autism spectrum disorder and occurs primarily among girls. Through this study, the researchers were able to connect the problems with droplet formation to an individual’s genetic predisposition to the disease.
The MECP2 has a region that binds to DNA and two arms, one of which binds with other proteins. According to the study, people affected with Rett syndrome exhibit mutations in the structured region, which reduce the protein’s ability to form droplets around DNA. When the droplets are disrupted, gene expression goes haywire. In other words, due to these mutations, cells are not able to express genes properly, which is seen in people with Rett syndrome.
However, not everyone is convinced of the study’s findings. According to Adrian Bird, Buchanan Professor of Genetics at the University of Edinburgh in Scotland and one of the pioneers of the bridge model of the MECP2 function, it is still unclear what phase transitions mean and how they add to our understanding of MECP2. He has criticised the study for not accurately representing the cellular environment, but he adds that he is prepared to be proven wrong with more data.
On the other hand, Wendy Gold, head of molecular neurobiology at the Children’s Hospital at Westmead in Sydney, Australia, if the new study’s findings prove to be accurate, this could result in a new treatment plan for Rett syndrome.
Qiang Chang, professor of medical genetics and neurology at the University of Wisconsin-Madison, says that the study’s findings are a stepping stone. The next step should be to see how to manipulate the MECP2 droplets and the molecular bridge separately, allowing the researchers to fully understand the mechanisms that play a role in gene expression and how their dysfunction contributes to Rett syndrome.
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