CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-gamma locus.

How cell type-specific differences in chromatin conformation are achieved and their contribution to gene expression are incompletely understood. Here we identify a cryptic upstream orchestrator of interferon-gamma (IFNG) transcription, which is embedded within the human IL26 gene, compromised of a single CCCTC-binding factor (CTCF) binding site and retained in all mammals, even surviving near-complete evolutionary deletion of the equivalent gene encoding IL-26 in rodents. CTCF and cohesins occupy this element in vivo in a cell type-nonspecific manner.

Retroviral vectors: new applications for an old tool.

Retroviral vectors (RVs) have been used for stable gene transfer into mammalian cells for more than 20 years. The most popular RVs are those derived from the Moloney murine leukaemia virus (MoMLV). One of their main limitations is their inability to transduce noncycling cells.

Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells.

How T cells regulate interleukin 4 (IL-4) expression is not completely understood. We show here that single-positive thymocytes express IL-4, but attenuate GATA-3 expression, recruit DNA methyltransferases (Dnmts) to the Il4-Il13 locus and downregulate IL-4 expression as they mature into T cells. Type 2 polarization blocks Dnmt1 recruitment, enhances histone H3 Lys4 methylation (indicative of accessible chromatin) and initiates DNA demethylation of the locus.

Epigenetic regulation of T cell fate and function.

During their development, T lymphocytes make sequential cell fate choices: T rather than B lymphocytes, then TCRalphabeta or TCRgammadelta, CD4 or CD8, and Th1 or Th2 lineage. These fate choices require the initiation of new programs of gene expression, and once initiated, these programs must be faithfully propagated in a heritable manner from parental cells to their progeny. With the exception of the T cell receptor, these changes in gene expression occur without a change in information encoded directly in the DNA sequence.

A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.

The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells.