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Histone methylation mediated by NSD1 is required for the establishment and maintenance of neuronal identities [WGBS]

ABSTRACT: The formation of the mammalian neocortex during development requires coordinated establishment of functional regions at proper anterior-posterior and medial-lateral positions – area patterning, as well as neocortical layers. Although key transcription factors (TFs) were known to specify and maintain cell fates, mechanisms underlying how TFs are precise expressed and repressed are largely elusive. Here we showed that NSD1, the methyltransferase for histone H3 lysine 36 dimethylation (H3K36me2), controls both areal and layer identities of the neocortex. Nsd1-ablated neocortex showed prominent areal shift of all four primary functional regions and aberrant wiring of major cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning and coordination, reminiscent of patients with the Sotos syndrome carrying NSD1 mutations. Although projection neurons (PN) of neocortical layers were mostly properly produced and positioned upon Nsd1 deletion, post-mitotic PNs could not establish their layer-specific identities. More strikingly, in adult Nsd1 conditional knockout neocortices, superficial-layer PNs progressively mis-expressed markers for deep-layer PNs. Moreover, neocortical PNs ablated with Nsd1 remained immature morphologically and electrophysiologically. Loss of NSD1 in post-mitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Our findings revealed that H3K36me2 mediated by NSD1 is required for establishment and maintenance of region- and layer-specific neocortical identities.

ORGANISM(S): Mus musculus

PROVIDER: GSE229340 | GEO | 2024/01/18

REPOSITORIES: GEO

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Project description:Genome-wide transcriptional profiling allows characterization of the molecular underpinnings of neocortical organization, including cortical areal specialization, laminar cell type diversity and functional anatomy. Microarray analysis of individual cortical layers across sensorimotor and association cortices in rhesus macaque demonstrated robust and specific laminar and areal molecular signatures driven by differential expression of genes associated with specialized neuronal function. Gene expression corresponding with laminar architecture was generally similar across cortical areas, although genes with robust areal patterning were often highly laminar as well, and these patterns were more highly conserved between macaque and human as compared to mouse. Layer 4 of primate primary visual cortex displayed a distinct molecular signature compared to other cortical regions, a specialization not observed in mouse. Overall, transcriptome-based relationships were strongest between proximal layers in a cortical area, and between neighboring areas along the rostrocaudal axis, reflecting in vivo cortical spatial topography and therefore a developmental imprint. Tissue from male and female monkeys (n = 2-3 animals/gender) was collected from anterior cingulate gyrus (ACG), layers 2, 3, 5, 6; orbitofrontal cortex (OFC), layers 2, 3, 5, 6; dorsolateral prefrontal cortex (DLPFC), layers 2-6; primary motor cortex (M1), layers 2, 3, 5, 6; primary somatosensory cortex (S1), layers 2-6; primary auditory cortex (A1), layers 2-6; primary visual cortex (V1), layers 2-6 including 4A, 4B, 4Calpha (4Ca), 4Cbeta (4Cb); secondary visual cortex (V2), layers 2-6; middle temporal area (MT), layers 2-6; temporal area (TE), layers 2-6; hippocampus, CA1, CA2, CA3, dentate gyrus (DG); and dorsal lateral geniculate nucleus (LGN), magnocellular, parvocellular and koniocellular divisions. Due to the limited number of samples that could be amplified concurrently, amplifications were performed in 3 batches (batches A-C, containing 102, 119 and 10 experimental samples, respectively). To control for batch effects, common RNA pool control samples were amplified and hybridized in each batch. These included LCM extracted hippocampus CA3 samples from the current study and a whole rhesus brain RNA pool (Biochain). These control samples were hybridized in 6 replicates in batch A and B and in 3 replicates in batch C (3 replicates per 96 well plate).

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Histone methylation mediated by NSD1 is required for the establishment and maintenance of neuronal identities [WGBS]

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