PubMed · 9092262
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J Engel. 1996. Epilepsy: structural or functional?. https://pubmed.ncbi.nlm.nih.gov/9092262/
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DNA packaging into heterochromatin is a fundamental mechanism of transcriptional silencing, yet its role in regulating neural progenitor behavior during brain development remains poorly understood. Trimethylation of histone H3 lysine 9 (H3K9me3), catalyzed by the methyltransferases SETDB1, SUV39H1, and SUV39H2, is a defining feature of heterochromatin, but functional redundancy among these enzymes has obscured their developmental roles. Here, we generated a cortex-specific triple knockout mouse model lacking Setdb1, Suv39h1, and Suv39h2 to directly interrogate H3K9me3 function during corticogenesis. Combined loss of H3K9 methyltransferases caused genome-wide depletion of H3K9me3, disruption of neural progenitor cell-cycle progression, and impaired cortical neurogenesis, resulting in microcephaly. H3K9 methyltransferases preserve neural progenitor identity and function by silencing clustered protocadherins, meiosis-associated genes, and a cell-cycle restraint program through H3K9me3 deposition. Loss of H3K9me3 promoted local chromatin opening and increased transcription factor occupancy, enabling transposable elements to acquire cryptic enhancer activity and modulate proximal gene expression. Together, these findings establish H3K9me3 heterochromatin as an active regulator of neural progenitor dynamics and lineage fidelity, revealing a central epigenetic mechanism that restricts aberrant transcriptional programs to ensure cortical growth.
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Cholinergic neurons originating in the basal forebrain innervate all cortical areas and participate in the gating of cortical information processing. Aberrations in the excitability of cortical cholinergic inputs fundamentally alter the processing of sensory stimuli and higher processes, thereby advancing the development of major neuropsychiatric disorders. Cortical cholinergic deafferentation has been considered to be a major neuropathological variable that contributes to the development of age- and dementia-associated impairments in cognition. Conversely, it has been suggested that increases in the excitability of cortical cholinergic inputs mediate the abnormal cognitive processes that escalate into psychotic symptoms and contribute to addictive-drug-seeking behavior, anxiety and phobia. Abnormal regulation of the excitability of cortical cholinergic afferents represents a 'final common pathway' that mediates the manifestation of major neuropsychiatric disorders.