Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder that is mainly caused by mutations in the methyl-DNA-binding protein MECP2. MECP2 is an important epigenetic regulator that plays a pivotal role in neuronal gene regulation, where it has been reported to function as both a repressor and an activator. Despite extensive efforts in mechanistic studies over the past two decades, a clear consensus on how MECP2 dysfunction impacts molecular mechanisms and contributes to disease progression has not been reached. Here, we review recent insights from epigenomic, transcriptomic and proteomic studies that advance our understanding of MECP2 as an interacting hub for DNA, RNA and transcription factors, orchestrating diverse processes that are crucial for neuronal function. By discussing findings from different model systems, we identify crucial epigenetic details and cofactor interactions, enriching our understanding of the multifaceted roles of MECP2 in transcriptional regulation and chromatin structure. These mechanistic insights offer potential avenues for rational therapeutic design for RTT.
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Acknowledgements
The authors thank L. Laurent and M. Oulmou for their valuable insights into the role of MECP2 in non-neuronal cells, DNA damage, RNA splicing and post-transcriptional regulation. All figures were created using BioRender. This work was supported by NIH grant 5R01MH104610 (R.J.) and International Rett Syndrome Foundation Research Independence Award (Y.L.). This research was supported by a generous gift from The Owens Family Foundation (Y.L. and R.J.).
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Y.L., R.G., T.W.W. and G.W.B. researched data for the article. Y.L., R.G., R.A.Y. and R.J. contributed substantially to discussion of the content. Y.L., T.W.W., G.W.B., R.G. and A.F. wrote the article. All authors reviewed and/or edited the manuscript before submission.
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R.J. is an adviser and co-founder of Fate Therapeutics and Fulcrum Therapeutics. A.F. is a co-founder and shareholder of StemAxon. R.A.Y. is a founder and shareholder of Syros Pharmaceuticals, Camp4 Therapeutics, Omega Therapeutics, Dewpoint Therapeutics and Paratus Sciences. All other authors declare no competing interests.
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Glossary
- AT hooks
-
DNA-binding motifs targeting the minor groove of AT-rich DNA.
- Chromatin
-
A mixture of DNA and proteins, primarily histones, that forms the chromosomes within the nucleus of a eukaryotic cell.
- Chromatin loops
-
Structures formed by the folding of chromatin fibres and anchored by specific proteins such as CTCF and cohesin complexes, these bring distinct regions on the same chromosome closer to each other.
- Condensates
-
Membraneless compartments formed by phase separation of biomolecules including proteins and nucleic acids.
- DNA damage repair
-
A process by which cells identify and correct damages to DNA molecules, thereby restoring genomic integrity.
- Enhancer
-
A short regulatory DNA sequence that is in close spatial proximity to its target genes and can be bound by transcription factors to increase the transcription of its targets.
- Gene body
-
The region of the gene that starts at the transcription start site and extends to the transcription termination site, including both exons and introns.
- Heterochromatin
-
A type of chromatin that is densely packed and transcriptionally inactive.
- Long genes
-
Genes that are longer than 100 kb. These genes are crucial for the development and function of neurons, which contain longer transcripts in the transcriptome than non-neuronal cells.
- MicroRNAs
-
Non-coding RNAs that regulate gene expression by binding to and influencing mRNA targets in diverse biological processes.
- Microsatellites
-
Short, repetitive DNA sequences consisting of 1–6 bp motifs, which are scattered throughout the genome.
- Microtubule
-
A hollow polymeric tube composed of tubulin that helps support the shape of a cell.
- Nucleosome
-
The basic repeating subunit of chromatin consisting of a section of DNA wrapping around a histone octamer.
- Post-transcriptional regulation
-
Processes that control gene expression at the RNA level, between transcription and translation, primarily including capping, splicing, polyadenylation and nuclear export.
- Promoter
-
A regulatory DNA sequence that is located upstream of its target gene and can be bound by RNA polymerase II and transcription factors to initiate the transcription of its targets.
- RNA splicing
-
A biological process in which a newly transcribed precursor mRNA is modified by removing introns and rejoining exons to produce a mature mRNA that can be translated into a protein.
- Topologically associating domains
-
Fundamental units of 3D nuclear DNA organization in which cis-regulatory elements and their targets can frequently interact.
- Transcription start sites
-
Locations on a DNA molecule at which the first nucleotide is transcribed into RNA.
- X chromosome inactivation
-
A dosage compensation mechanism in female mammals, where one of the two X chromosomes in each cell is randomly silenced to equalize the expression of X-linked genes between males and females.
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Liu, Y., Whitfield, T.W., Bell, G.W. et al. Exploring the complexity of MECP2 function in Rett syndrome. Nat. Rev. Neurosci. 26, 379–398 (2025). https://doi.org/10.1038/s41583-025-00926-1
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DOI: https://doi.org/10.1038/s41583-025-00926-1
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