| Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2011: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
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| Research Abstract |
Naive CD4 T cells differentiate into two major subsets of helper T cells, Th1 and Th2, which are defined based on their non-overlapping cytokine profiles and immunoregulatory functions. Th1 cells secrete IFN-γ and TNF-α and are responsible for cell-mediated immunity and protection against intracellular pathogens, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13, and mediate humoral immunity and protection against helminthic infection. The mouse Th2 cytokine locus contains Il4, Il5, Il13, and the constitutively expressed Rad50 and Kif3a genes, and the locus composition is well conserved in mammals. Th2 cytokine expression is heritably regulated by transcriptionally permissive and repressive chromatin structure at cis-acting regulatory elements, which have been experimentally identified by the detection of DNaseI hypersensitive(HS) sites and histone modifications. In the mouse Th2 locus, Il4 transcription is regulated by elements that map to conserved sequence 1(HSS1 and HSS2
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), located between Il13 and Il4, HS0, located in the 5' region of Il4, HS1, located in the promoter region, HS2 and HS3 in the second exon, and HS5a and HS5, located 3' of Il4. The Il13 locus contains two promoter regions, HS1 and HS2. HS1 is the conserved GATA-3 response element(CGRE) upstream of the proximal promoter, HS2. Studies of IL-4 regulatory elements in mice with a germline deletion of these regulatory regions still leave open the question of whether each element regulates Il4 transcription or Th2 differentiation. Our study demonstrates that HS2 in the Il4 locus is a critical GATA-3 binding site that regulates lineage specific IL-4 expression. Deletion of HS2 markedly impaired maintenance of H3K9/K14 acetylation and the onset of H3K4 methylation on the Il4 locus, both of which are required for transcriptional permissibility, leading to the lack of Il4 transcription. GATA-3 overexpression failed to reconstitute these defects. We found that HS2, as a specific target of the GATA-3 mediated epigenetic modification on the Il4 locus, is an indispensable enhancer. Therefore, we found a novel regulation of Th2 cytokine genes by GATA-3 protein. Less
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