Spatially resolved mapping of histones reveals selective neuronal response in Rett syndrome

Rett syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in the X-linked Mecp2 gene, results in profound life-long neurological dysfunction. Rett syndrome patients live an apparently normal initial life until 12–18 months of age, after which a progressive accumulation of a wide range of phenotypic manifestations sets in. While MeCP2 is known to regulate chromatin, its impact on global histone composition and dynamics remains poorly understood. Here, we combine mass spectrometry imaging (MSI) and laser capture microdissection (LCM) coupled to LC–MS/MS to systematically profile histone proteoforms in three key brain regions: the dentate gyrus (DG) and cornu ammonis (CA) of the hippocampus, and the cerebellum (Cb). Our analysis reveals striking neuron-specific differences in histone composition between Mecp2-deficient and wild-type (WT) mice. Interestingly, the expression of a pathogenic Mecp2 missense mutant (Y120D) results in subtler changes in histone composition that are distinct from the null mutation. This study provides the first spatially resolved epigenetic atlas of histone proteoforms in Rett syndrome and suggests that Mecp2 loss perturbs chromatin homeostasis in a neuron- and mutation-dependent manner. Our findings underscore the critical need for cell-type-resolved analyses to unravel the mechanistic underpinnings of Rett syndrome and emphasize the importance of personalized therapeutic strategies that consider both the affected cell type and particular Mecp2 mutation.