期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 281, 期 19, 页码 13604-13611出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M513278200
关键词
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资金
- NCI NIH HHS [R01 CA086978-03, R01 CA086978-02, R01 CA086978, R01 CA086978-01A2, R01 CA086978-05, R01 CA086978-06A1, CA 86978, R01 CA086978-04] Funding Source: Medline
- NIEHS NIH HHS [R01 ES010874-02, ES 10874, R01 ES010874-04, R01 ES010874, R01 ES010874-03, R01 ES010874-05, R01 ES010874-01] Funding Source: Medline
Previously we showed that DNA methyltransferase 3b (Dnmt3b) is required for nerve growth factor (NGF)- induced differentiation of PC12 cells to neuronal phenotype. The present study identified T-cadherin (T-Cad) as one of the targets of Dnmt3b by chromatin immunoprecipitation (ChIP) assay. Combined bisulfite restriction analysis and bisulfite sequencing showed that T- Cad promoter was sparsely methylated in PC12 cells. ChIP-CHOP analysis demonstrated that Dnmt3b is associated with T-Cad promoter irrespective of its methylation status. The mRNA and protein levels of T-Cad were markedly elevated in cells depleted of Dnmt3b by antisense or small interfering RNA. Suppression of T- Cad promoter activity by Dnmt3b was independent of its catalytic activity, which was consistent with the insignificant change in T-Cad promoter methylation status in Dnmt3b-depleted cells. In contrast, deletion of its N-terminal ATRX and PWWP domain abolished its repressor function. Association of histone deacetylase 2 (Hdac2) with T-Cad promoter and restoration of the promoter activity from Dnmt3b-mediated suppression upon treatment with Hdac inhibitor indicated involvement of histone deacetylation in this process. NGF-induced neurite outgrowth was inhibited in a dose dependent manner upon ectopic expression of T-Cad in PC12 cells. Immunofluorescence studies showed that T-Cad was redistributed upon NGF treatment, as evident from its concentration in axon growth cones as opposed to its localization at cell-cell contact region in undifferentiated cells. These results demonstrate a novel role of T-Cad in the NGF-mediated differentiation of PC12 cells to neuronal phenotype.
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