Dataset Information

De novo DNA methylation by DNA Methyltransferase 3a controls early effector CD8+ T cell fate decisions following activation

ABSTRACT: DNMT3a is a de novo DNA methyltransferase expressed robustly after T cell activation that regulates plasticity of CD4+ T cell cytokine expression. Here we show that DNMT3a is critical for directing early CD8+ T cell effector and memory fate decisions. While effector function of DNMT3a knockout T cells is normal, they develop more memory precursor and fewer terminal effector cells in a T cell intrinsic manner compared to wild-type animals. Rather than increasing plasticity of differentiated effector CD8+ T cells, loss of DNMT3a biases differentiation of early effector cells into memory precursor cells. This is attributed in part to ineffective repression of Tcf1 expression in knockout T cells, as DNMT3a localizes to the Tcf7 promoter and catalyzes its de novo methylation in early effector WT CD8+ T cells. This data identifies DNMT3a as a crucial regulator of CD8+ early effector cell differentiation and effector versus memory fate decisions. Examination of global genomic DNA methylation by MBD-seq in naïve CD8 T cells and CD8 T cells 8 days post Vaccinia-Ova infection, comparing OT1 TCR-Tg CD8 T cells isolated from WT and T cell conditional DNMT3a KO mice.

ORGANISM(S): Mus musculus

SUBMITTER: David A Hildeman Kun-Po Li Azeb Haile Christopher Jordan Gamper Elizabeth M Jaffee Christopher J Gamper Jonathan D Powell Alexandra B Pucsek Maggie J Phillips Brian H Ladle

PROVIDER: E-GEOD-85823 | ArrayExpress | 2016-08-20

SECONDARY ACCESSION(S): GSE85823SRP082394PRJNA339495

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer.

Guerrero-Preston Rafael R Michailidi Christina C Marchionni Luigi L Pickering Curtis R CR Frederick Mitchell J MJ Myers Jeffrey N JN Yegnasubramanian Srinivasan S Hadar Tal T Noordhuis Maartje G MG Zizkova Veronika V Fertig Elana E Agrawal Nishant N Westra William W Koch Wayne W Califano Joseph J Velculescu Victor E VE Sidransky David D

Epigenetics 20140501 7

Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplast ...[more]

PMID: 24786473

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