Periodic Reporting for period 1 - 2CE MECP2 (Visualising neuronal signalling dynamics within intact neuronal circuits: Deciphering the role of cell-specific MeCP2 dynamics in neuronal function and dysfunction)
Reporting period: 2022-10-01 to 2025-03-31
The brain has a remarkable capacity to undergo ongoing changes, which allow us to adapt to our environment. Brain plasticity depends on changes in specific subsets of genes, and one key mechanism that enables brain adaptation is epigenetic modification. These modifications involve physical changes to genes that regulate the activation or inhibition of specific genes through epigenetic modulators. One prominent example of such an epigenetic modulator is the gene MeCP2.
Previous studies have shown that MeCP2 is expressed at high levels in the brain and binds to specific regions across the genome. The importance of this gene in normal brain function has been highlighted through research on the rare and devastating neurodevelopmental disorder, Rett Syndrome. Patients with Rett syndrome are born without any prominent disabilities or neurological deficiencies during the early stages of development. However, between the ages of 1 and 2 years, the disease begins to manifest, leading to severe impairments in social, motor, sensory, and cognitive functions. Tragically, children with Rett syndrome experience a rapid deterioration in neurological abilities, which significantly shortens their lifespan.
Over 20 years ago, studies identified that Rett syndrome is genetically caused by mutations in the MeCP2 gene. A prominent question in neuroscience has been: How can mutations in a single gene lead to such devastating effects on brain development and function? Despite extensive research and a wealth of data on the role of MeCP2 in the brain, the precise function of MeCP2 in normal brain activity remains unclear. Understanding the normal function of MeCP2 is crucial for developing potential therapeutic strategies for Rett syndrome. Currently, despite numerous clinical efforts to develop gene therapies and drugs, Rett syndrome remains a progressive, devastating neurodevelopmental disorder, with no cure for patients.
Previous studies have shown that MeCP2 is expressed at high levels in the brain and binds to specific regions across the genome. The importance of this gene in normal brain function has been highlighted through research on the rare and devastating neurodevelopmental disorder, Rett Syndrome. Patients with Rett syndrome are born without any prominent disabilities or neurological deficiencies during the early stages of development. However, between the ages of 1 and 2 years, the disease begins to manifest, leading to severe impairments in social, motor, sensory, and cognitive functions. Tragically, children with Rett syndrome experience a rapid deterioration in neurological abilities, which significantly shortens their lifespan.
Over 20 years ago, studies identified that Rett syndrome is genetically caused by mutations in the MeCP2 gene. A prominent question in neuroscience has been: How can mutations in a single gene lead to such devastating effects on brain development and function? Despite extensive research and a wealth of data on the role of MeCP2 in the brain, the precise function of MeCP2 in normal brain activity remains unclear. Understanding the normal function of MeCP2 is crucial for developing potential therapeutic strategies for Rett syndrome. Currently, despite numerous clinical efforts to develop gene therapies and drugs, Rett syndrome remains a progressive, devastating neurodevelopmental disorder, with no cure for patients.
In this project, we aimed to develop a novel approach to visualize the activity of MeCP2 in the brain. Our goal was to use this tool to expand our understanding of MeCP2 activity and regulation in the healthy brain. Ultimately, we hoped these findings would help us gain further insight into how MeCP2 dysfunction leads to Rett syndrome.
We successfully engineered a new experimental approach that combined molecular, genetic, and optical techniques, allowing us to monitor MeCP2 and its interactions with other proteins within living cells. This approach led to the discovery of a specific function of MeCP2 that was previously unknown. We found that MeCP2 plays a crucial role in maintaining the integrity of the genome under ongoing stress.
Genes are constantly exposed to internal and external stressors that can cause DNA damage. Cells have dedicated machinery to continuously repair DNA damage and breaks, ensuring the survival and integrity of cellular function. Our findings suggest that MeCP2 is vital for maintaining genomic integrity in response to external changes in sensory experiences, which in turn lead to changes in neuronal activity.
Based on this, we hypothesize that mutations or reductions in MeCP2 activity may lead to the accumulation of DNA damage. To test this, we analysed the levels of DNA double-strand breaks, which represent some of the most severe forms of genomic damage. We found that genetic deletion of the MeCP2 gene in cells resulted in a significant accumulation of DNA breaks compared to cells with normal MeCP2 function.
We are continuing this work to explore whether supplying agents that can protect and expedite DNA repair might mitigate or reverse the impact of MeCP2 disruption. This approach could potentially lead to future therapies aimed at restoring brain function in Rett syndrome.
We successfully engineered a new experimental approach that combined molecular, genetic, and optical techniques, allowing us to monitor MeCP2 and its interactions with other proteins within living cells. This approach led to the discovery of a specific function of MeCP2 that was previously unknown. We found that MeCP2 plays a crucial role in maintaining the integrity of the genome under ongoing stress.
Genes are constantly exposed to internal and external stressors that can cause DNA damage. Cells have dedicated machinery to continuously repair DNA damage and breaks, ensuring the survival and integrity of cellular function. Our findings suggest that MeCP2 is vital for maintaining genomic integrity in response to external changes in sensory experiences, which in turn lead to changes in neuronal activity.
Based on this, we hypothesize that mutations or reductions in MeCP2 activity may lead to the accumulation of DNA damage. To test this, we analysed the levels of DNA double-strand breaks, which represent some of the most severe forms of genomic damage. We found that genetic deletion of the MeCP2 gene in cells resulted in a significant accumulation of DNA breaks compared to cells with normal MeCP2 function.
We are continuing this work to explore whether supplying agents that can protect and expedite DNA repair might mitigate or reverse the impact of MeCP2 disruption. This approach could potentially lead to future therapies aimed at restoring brain function in Rett syndrome.
Our results offer a new perspective on the role of MeCP2 in the normal brain. Using a novel technology we developed, we were able to uncover the activity of MeCP2 in the live brain for the first time. Importantly, we found that deletion or mutations in MeCP2 lead to severe DNA damage in cells.
We are now expanding these findings in two key ways:
1. Developing improved optical approaches to measure DNA damage: These advancements will allow us to more precisely track how and when DNA damage occurs and accumulates in the healthy brain. Additionally, this will help us better understand how this process is altered in the context of MeCP2 dysfunction in Rett syndrome.
2. Testing genetic strategies to protect the genome and enhance DNA surveillance: By augmenting the cell's DNA repair mechanisms, we aim to reduce DNA breaks. This could pave the way for a targeted strategy to restore neuronal and brain function in Rett syndrome.
Both of these future directions will require continued funding and support to make significant progress and achieve these ambitious goals.
We are now expanding these findings in two key ways:
1. Developing improved optical approaches to measure DNA damage: These advancements will allow us to more precisely track how and when DNA damage occurs and accumulates in the healthy brain. Additionally, this will help us better understand how this process is altered in the context of MeCP2 dysfunction in Rett syndrome.
2. Testing genetic strategies to protect the genome and enhance DNA surveillance: By augmenting the cell's DNA repair mechanisms, we aim to reduce DNA breaks. This could pave the way for a targeted strategy to restore neuronal and brain function in Rett syndrome.
Both of these future directions will require continued funding and support to make significant progress and achieve these ambitious goals.