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PMID: 9653088 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Distinct methylation of the interferon gamma (IFN-gamma) and interleukin 3 (IL-3) genes in newly activated primary CD8+ T lymphocytes: regional IFN-gamma promoter demethylation and mRNA expression are heritable in CD44(high)CD8+ T cells.

The Journal of experimental medicine ·Vol. 188 ·No. 1 ·1998-07-06 ·Pages 103-17

Fitzpatrick DR, Shirley KM, McDonald LE, Bielefeldt-Ohmann H, Kay GF, Kelso A

Abstract

Differential genomic DNA methylation has the potential to influence the development of T cell cytokine production profiles. Therefore, we have conducted a clonal analysis of interferon (IFN)-gamma and interleukin (IL)-3 gene methylation and messenger (m)RNA expression in primary CD8+ T cells during the early stages of activation, growth, and cytokine expression. Despite similar distributions and densities of CpG methylation sites, the IFN-gamma and IL-3 promoters exhibited differential demethylation in the same T cell clone, and heterogeneity between clones. Methylation patterns and mRNA levels were correlated for both genes, but demethylation of the IFN-gamma promoter was widespread across >300 basepairs in clones expressing high levels of IFN-gamma mRNA, whereas demethylation of the IL-3 promoter was confined to specific CpG sites in the same clones. Conversely, the majority of clones expressing low or undetectable levels of IFN-gamma mRNA exhibited symmetrical methylation of four to six of the IFN-gamma promoter CpG sites. Genomic DNA methylation also has the potential to influence the maintenance or stability of T cell cytokine production profiles. Therefore, we also tested the heritability of IFN-gamma gene methylation and mRNA expression in families of clones derived from resting CD44(low)CD8+ T cells or from previously activated CD44(high)CD8+ T cells. The patterns of IFN-gamma gene demethylation and mRNA expression were faithfully inherited in all clones derived from CD44(high) cells, but variable in clones derived from CD44(low) cells. Overall, these findings suggest that differential genomic DNA methylation, including differences among cytokine genes, among individual T cells, and among T cells with different activation histories, is an important feature of cytokine gene expression in primary T cells.

MeSH Terms
Animals Azacitidine/pharmacology Base Sequence CD8-Positive T-Lymphocytes/immunology CpG Islands/genetics DNA Methylation/drug effects Female Gene Expression Regulation/genetics Hyaluronan Receptors/immunology Interferon-gamma/genetics Interleukin-3/genetics Mice Molecular Sequence Data Promoter Regions, Genetic/genetics RNA, Messenger/metabolism Sequence Analysis, DNA Sequence Homology, Nucleic Acid
Chemicals
Hyaluronan Receptors Interleukin-3 RNA, Messenger Interferon-gamma Azacitidine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Fitzpatrick D R
Leukocyte Biology Unit, The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Queensland 4029, Australia. davidf@qimr.edu.au
Shirley K M
McDonald L E
Bielefeldt-Ohmann H
Kay G F
Kelso A
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.188.1.103
Email
davidf@qimr.edu.au
Published
1998-07-06
Pages
103-17
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2525536
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.188.1.103 PMC Full Text View journal details
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