Language
English
Publication Date
11-28-2025
Journal
Science Advances
DOI
10.1126/sciadv.adt5937
PMID
41296873
PMCID
PMC12652325
PubMedCentral® Posted Date
11-26-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause Rett syndrome. While we know that MeCP2 binds to methylated cytosines on DNA, the full breadth of the molecular mechanisms by which MeCP2 regulates gene expression remains incompletely understood. Here, using a genetic modifier screen, we identify the super elongation complex, a P-TEFb–containing elongation factor that releases promoter-proximally paused RNA polymerase II, as a genetic interactor of MECP2. MeCP2 physically interacts with SEC subunits and directly binds AFF4, the scaffold of the SEC, via the transcriptional repression domain. Furthermore, MeCP2 facilitates the binding of AFF4 on a subset of genes in the mouse brain regulating synaptic plasticity and concordantly promotes the binding of RNA polymerase II on these genes. Last, while haploinsufficiency of Aff4 does not exhibit any behavioral deficits in mice, it exacerbates the impaired contextual learning behavior of Mecp2 hypomorphic mice. We propose a previously unknown mechanism by which MePC2 regulates gene expression underlying synaptic plasticity.
Keywords
Methyl-CpG-Binding Protein 2, Animals, Mice, Transcription, Genetic, Protein Binding, Humans, Gene Expression Regulation, RNA Polymerase II, Neuronal Plasticity, Rett Syndrome, Brain
Published Open-Access
yes
Recommended Citation
Sonn, Jun Young; Kim, Wonho; Iwanaszko, Marta; et al., "MeCP2 Interacts With the Super Elongation Complex To Regulate Transcription" (2025). Faculty and Staff Publications. 5025.
https://digitalcommons.library.tmc.edu/baylor_docs/5025
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons