| Budget Amount *help |
¥49,790,000 (Direct Cost: ¥38,300,000、Indirect Cost: ¥11,490,000)
Fiscal Year 2010: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Fiscal Year 2009: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
Fiscal Year 2008: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
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| Research Abstract |
Neurons, astrocytes and oligodendrocytes, three major cell types that consist the central nervous system, are derived from common neural stem cells(NSCs). Whereas NSCs generate neurons in the early stages of neocortical development, they lose the neurogenic potential and generate only glial cells in the late stages. In this study, we found "global" changes of the chromatin state in NPCs during neocortical development in addition to "local" changes at specific gene loci. Chromatins isolated from early-stage NSCs were less condensed compared to those from late-stage NSCs, as revealed by nuclease digestion and salt-extraction analyses, as well as by a fluorescent recovery after photobleaching(FRAP) analysis using histone H1-GFP. We also identified chromatin-binding proteins necessary for the "less condensed" state of the chromatin in early-stage NSCs. Importantly, knockdown of these proteins reduced the neurogenic capacity of early-stage NSCs, and conversely, their overexpression increase
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d neurogenesis and suppressed astrogenesis of late-stage NSCs. These results suggest that global chromatin condensation might contribute to the fate restriction of NSCs during neocortical development.
Recent studies have revealed various biological functions for repetitive sequences, which make up about half of the human genome. One such sequence, major satellites, which are tandem repetitive sequences adjacent to the centromere, have been shown to be a kinetochore component that plays a role in the formation and function of the pericentric heterochromatin necessary for mitosis. However, it is unknown whether these regions also play a role in post-mitotic cells. Here, we show that, during neuronal differentiation, the heterochromatin domains that include major satellite regions become both enriched with the active histone modification lysine-4 trimethylation of histone H3, and more sensitive to nuclease, both of which suggest increased activation of this area. Further supporting this notion, we also found that transcription from major satellite regions is significantly increased during neuronal differentiation both in vitro and in vivo. These results together suggest that the structural and transcriptional state of major satellite regions changes dramatically during neuronal differentiation, implying that this region might play a role in differentiating neurons. Less
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