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Rett syndrome patients live an apparently normal initial life until 12\u201318\u2009months 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\u2013MS\/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\u2010specific differences in histone composition between Mecp2\u2010deficient and wild\u2010type (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\u2010 and mutation\u2010dependent manner. Our findings underscore the critical need for cell\u2010type\u2010resolved 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.\n                  <\/jats:p>","DOI":"10.1111\/febs.70534","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T13:43:39Z","timestamp":1775051019000},"page":"5814-5836","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Spatially resolved mapping of histones reveals selective neuronal response in Rett syndrome"],"prefix":"10.1111","volume":"293","author":[{"given":"Frederike","family":"Sch\u00e4fer","sequence":"first","affiliation":[{"name":"Biomedical Center Munich, Department of Molecular Biology, Faculty of Medicine Ludwig\u2010Maximilians Universit\u00e4t M\u00fcnchen  Planegg\u2010Martinsried 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