The MIT team reveals the new mechanism of Rett syndrome, and the related neuron

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The reviewer believes that this work will set a new milestone in the field of genetics of Rett syndrome. It points out that this paper will fundamentally change people's understanding of MECP2 causing Rett syndrome, said Liu Yi, a doctoral graduate from the University of Toronto, Canada, who is currently engaged in postdoctoral research at the Massachusetts Institute of Technology in the United States.

Through this study, he and his team have provided a new understanding of the binding patterns of MECP2 on the human neuronal genome, its mode of action, and its impact on gene transcription, demonstrating the great potential of MECP2 as a key transcriptional activator.

At the same time, Liu Yi and his team have also established a whole-genome epigenetic map of MECP2.

Through this map, they were pleasantly surprised to find that MECP2 directly binds with more than 4,000 neuronal genes. Even more exciting is that many of them are related to autism.

In terms of molecular mechanisms, they found that MECP2 can directly interact with RNA polymerase II, thereby mediating transcriptional activation.According to the introduction, in the neurons of Rett syndrome, mutations in MECP2 reduce its binding affinity to target genes, leading to a decrease in the aggregation of RNA polymerase II at the transcription start site.

At the whole genome level, this change will lead to a reduction in the expression of related genes. By studying this change, the research group has elucidated a new pathogenic mechanism of Rett syndrome.

Early data suggest that in the Rett syndrome mouse model lacking the MECP2 gene, when the expression of the MECP2 gene in the mouse brain is restored, it can repair neural dysfunction to a certain extent.

In the study, they found that MECP2 can bind and directly regulate 4189 genes in human neurons. Among them, 381 genes are related to the risk of autism.

In neurons carrying the gene mutations of Rett syndrome patients, about 80% of MECP2 can directly regulate genes and will be downregulated in transcription, thereby causing obstacles in aspects such as neural development, synapse formation, mitochondrial, ribosomal, and ciliary function.Based on this, they identified the disordered cellular pathways directly caused by MECP2 gene mutations, which have the potential to become therapeutic targets for small molecule drug screening.

At the molecular mechanism level, they found that most MECP2 Rett syndrome gene mutations weaken the interaction between MECP2 and RNA polymerase II, thereby reducing the aggregation of RNA polymerase II at the transcription start site and hindering gene expression.

Therefore, the protein-protein interaction between MECP2 and RNA polymerase II may become an important target for the treatment of Rett syndrome and can address the gene expression disorders in neurons from a molecular mechanism perspective.

The comprehensive epigenetic genome gene map of MECP2 in healthy and disease states constructed by the team can be used to guide the targeted treatment of Rett syndrome.

Overall, this discovery is expected to change people's understanding of the function of MECP2 molecules, not only bringing a new perspective for understanding its mechanism of action, but also providing valuable clues for the development of related treatment methods.The 20-year-old enigma of Rett syndrome

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It is understood that Rett syndrome is a rare neurodevelopmental disorder that leads to severe intellectual disabilities, language disorders, motor disorders, and behaviors similar to those on the autism spectrum.

This disease is mainly caused by mutations in the MECP2 gene located on the X chromosome, and it usually begins to manifest in the early childhood of girls, and there is currently no cure.

The MECP2 protein encoded by the MECP2 gene is highly expressed in the brain. Therefore, this protein is an important epigenetic regulator that plays a crucial role in maintaining neuronal function.

Since the discovery of MECP2 gene mutations causing Rett syndrome in humans in 1999, global researchers, including the team of Liu Yi's postdoctoral supervisor, American Academy of Sciences member, and Massachusetts Institute of Technology professor Rudolf Jaenisch, have conducted in-depth research for more than 20 years.Despite the fact that people have already understood that MECP2 gene mutations have a widespread impact on the regulation of neuronal gene expression,

the human race has not yet fully clarified which genes MECP2 protein can directly bind to, and the pathogenesis of Rett syndrome caused by the changes in the transcription of these genes.

Addressing these issues is crucial for the development of more targeted treatment plans.

Open source multi-omics databases are available for free use by everyone.To investigate the aforementioned issues, Liu Yi first needs to construct a model of Rett syndrome using human embryonic stem cells.

By utilizing CRISPR/Cas9 technology, he has constructed a structure with a green fluorescent protein tag at the endogenous MECP2 gene locus in human embryonic stem cells.

He has introduced MECP2 gene mutations commonly found in Rett syndrome patients and has also constructed human embryonic stem cells with MECP2 gene knockout.

Using highly specific green fluorescent protein antibodies, it is possible to directly compare the localization and functional differences between wild-type MECP2 protein and mutant MECP2 protein in cells.

For human embryonic stem cells, when using traditional methods to differentiate into mature neurons, it may take several months, and there may be significant heterogeneity in the resulting cell population.To efficiently induce neuronal differentiation, Liu Yi and his colleagues utilized the CRISPR/Cas9 technology to introduce a doxycycline-inducible NGN2 overexpression system into human embryonic stem cells.

The NGN2 gene encodes a neuron-specific transcription factor that can drive the differentiation of stem cells into neurons.

Therefore, by inducing the expression of the NGN2 gene, it takes less than three weeks to efficiently induce the differentiation of a mature neuronal population, and these neuronal populations have a high degree of uniformity.

In this way, the molecular mechanisms of MECP2 protein can be studied from the perspectives of neuronal development and pathological changes.

After establishing the Rett syndrome neuronal model, Liu Yi and others also optimized the application of the CUT&Tag technology in neurons.They utilized a highly specific green fluorescent protein antibody to enhance the experimental resolution. Subsequently, they began to analyze and compare the binding differences of wild-type MECP2 protein and mutant MECP2 protein on the neuronal genome.

In addition, they combined proteomics, whole-genome DNA methylation sequencing, chromatin accessibility sequencing, and RNA sequencing technology to construct an epigenetic map of MECP2 in human neurons.

To facilitate the sharing of multi-omics databases more conveniently, Liu Yi created an open-source data website called MECP2 NeuroAtlas ().

This allows industry insiders to perform bioinformatics analysis on raw data without spending too much time.

When using it, just enter a gene to explore the epigenome and proteome databases, thereby revealing the occupancy of MECP2 and RNA polymerase II on the selected gene, chromatin accessibility, and DNA methylation status.On this website, Liu Yi also provided a detailed chart, which lists the gene expression of selected genes in normal neurons and Rett syndrome neurons, as well as the potential protein interactions with wild-type MECP2 and mutant MECP2, respectively.

Ultimately, the relevant paper of this study was published in Neuron (IF 16.2) with the title "MECP2 directly interacts with RNA polymerase II to modulate transcription in human neurons."

Liu Yi is the first author, and Professor Rudolf Jaenisch from the Massachusetts Institute of Technology (MIT) served as the corresponding author.

Striving together with his wife at MITIn order to further elucidate the interaction mechanism between MECP2 and RNA polymerase II, as well as its impact on gene regulation, Liu Yi and his team plan to combine structural biology techniques with super-resolution microscopy technology to study the molecular mechanism of MECP2 binding to RNA polymerase II proteins.

They hope to explain the interaction between MECP2 gene mutations related to Rett syndrome and RNA polymerase II proteins. At the same time, they also hope to provide a certain molecular structural basis for the design of small molecule drugs for Rett syndrome.

As mentioned earlier, Liu Yi developed the MECP2 NeuroAtlas website, and he hopes to expand this model in the future and add more gene sequencing data.

At the same time, he will also make the open data platform bigger and stronger, promoting multi-omics research cooperation in the field of neuroscience.

In the meantime, he also hopes to establish an AI-based model to continue exploring the interaction mechanism between MECP2, RNA polymerase II, and DNA, and will verify it through structural biology methods.In the field of clinical prediction, he hopes to use AI models to predict how MECP2 gene mutations in patients affect their interactions with RNA polymerase II and DNA.

Further, he aims to predict the correlation between this impact and the severity of Rett syndrome, thereby gaining a better understanding of the disease mechanism and providing predictive tools for clinical use.

Liu Yi's journey into scientific research can be traced back to his learning experience at West China Hospital during a summer vacation. Later, he obtained his Ph.D. from the University of Toronto in Canada.

He said: "Another reason that propelled me towards the path of scientific research is my wife, Erika Wang. Erika is incredibly intelligent and yet very hardworking. We have known each other since our teens and have been together for more than ten years now. Trying to keep up with her pace has been a wonderful motivation for me," said Liu Yi.

After graduating from the University of Toronto in Canada, he, his wife, and their 10-year-old dog, Jacob, moved to Boston, USA.Liu Yi said: "Erika is now working as a Banting Fellow in the laboratory of Robert S. Langer at the Massachusetts Institute of Technology, engaged in translational medical research using engineering methods, while I focus on basic scientific research. In the future, we both hope to have our own independent research groups."