PubMed · 15569885
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Carol A Tamminga, Monte S Buchsbaum. 2004. Frontal cortex function.. https://doi.org/10.1176/appi.ajp.161.12.2178
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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.
BACKGROUND: Tuberous sclerosis complex (TSC) is an inherited disorder characterized by the presence of cortical tubers, the majority of which are solid and show high signal on FLAIR images. Low-signal tubers are less frequent. OBJECTIVE: To evaluate cystic cortical tubers in patients with TSC on the basis of their appearance on FLAIR images. MATERIALS AND METHODS: MR examinations of 73 patients were retrospectively reviewed and 17 children (aged 25 days to 12.3 years) with a typical cyst-like tubers were selected for further analysis. The age of the patients, the number of lesions, and the shape and MR intensity were analyzed. RESULTS: Cyst-like cortical tubers were detected in 82% of children below 7 years of age and in 18% of those older then 7 years (P=0.00086). Most of the cystic lesions were of the shrunken type (72%), the expansile type being less frequently seen (28%). CONCLUSIONS: FLAIR images confirm the cystic character of some of the cortical tubers in TSC patients although the pathogenesis of cystic change is still unknown.
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