Inhibition of IFN-[gamma] promoter function by site-specific methylation

When they become activated, naive helper T cells are able to polarize into either THI cells or TH2 cells. Development of naive CD4+ T cells into TH1 cells is characterized by the expression of IFN-y and the silencing of IL-4, while development into TH2 cells is characterized by expression of IL-4 and silencing of IFN-y. Naive helper T cells are hypomethylated at the IFN-y proximal promoter and hypermethylated at the contiguous transcribed region. During THI polarization, the promoter remains hypomethylated, while the transcribed region becomes demethylated. During TH2 polarization, the promoter undergoes progressive de novo methylation while the transcribed region remains hypermethylated. Notably, TH2 de novo methylation occurs at different rates at different CpG positions, with methylation occurring fastest at the CpG located at the -53 position relative to the transcription start site. Methylation at this position inhibits c-Jun, ATF2 and CREB binding in vitro. Consistently, the same factors bind to the unmethylated promoter in a TH1 cell line, but not the methylated promoter in a TH2 cell line. Furthermore, methylation of the proximal promoter at the -53 position alone is sufficient to inhibit promoter activity in transient transfection assays.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2006

Author dc:creator

• Jones, Brendan T. (Brendan Taber)

Advisor dc:contributor.advisor

• Jianzhu Shen.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/34188
• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Identifier URI

http://dspace.mit.edu/handle/1721.1/34188

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/34188