{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMECP2 is a multifunctional chromatin‐associated protein that interprets DNA methylation signatures, binding not only 5-methylcytosine but also 5-hydroxymethylcytosine with high affinity. Early work showed that MECP2 preferentially occupies methylated and hydroxymethylated DNA regions—including sites in gene bodies that affect alternative splicing—by recruiting transcriptional corepressors (for example, the NCoR/SMRT complex) and other chromatin modulators. In addition, MECP2 can influence chromatin architecture through its AT-hook domains and its capacity to form dynamic, liquid-like condensates, and it also interacts with chromatin remodelers such as ATRX. These observations established MECP2 as more than a simple silencer of methylated promoters, instead revealing a diverse capacity to modulate transcription in a context-dependent manner."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn neurons, MECP2 plays critical roles in promoting appropriate development and synaptic plasticity. Functionally, it regulates the expression of long genes and modulates activity-dependent signaling pathways—such as those linked to AKT/mTOR and ERK—and its deficiency has been shown to alter dendritic spine density, neurotransmitter synthesis, and neurite outgrowth. MECP2 also limits the mobilization of retrotransposons in neuronal progenitors, thereby contributing to the stability of the neuronal genome. Studies using both stem cell–derived neurons and animal models have demonstrated that loss of MECP2 perturbs these signaling cascades and impairs synaptic transmission, ultimately affecting neuronal maturation and circuit formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, MECP2 dosage appears to be exquisitely balanced; both loss-of-function mutations and increased gene dosage lead to distinct neurodevelopmental disorders. In addition to its cell-autonomous effects in neurons, MECP2 influences non–cell-autonomous mechanisms—for example, in astrocytes where its dysfunction alters neurotrophic factor production—and its disruption is linked to diverse clinical presentations such as Rett syndrome, MECP2 duplication syndrome, and features of autism and intellectual disability. Recent genetic and clinical studies have highlighted that mutations in MECP2 or its aberrant expression can alter neuronal migration and synaptic connectivity, while the identification of a novel isoform as well as interactions with proteins like CDKL5 broaden the scope of its regulatory network. Such findings underscore the importance of tightly regulated MECP2 function for normal brain physiology and development, as well as for other tissue-specific contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marian Mellén, Pinar Ayata, Scott Dewell, et al. 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