10 research outputs found
Changes in Chromatin Accessibility Across the GM-CSF Promoter upon T Cell Activation Are Dependent on Nuclear Factor κB Proteins
Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a key cytokine in myelopoiesis and aberrant expression is associated with chronic inflammatory disease and myeloid leukemias. This aberrant expression is often associated with constitutive nuclear factor (NF)-κB activation. To investigate the relationship between NF-κB and GM-CSF transcription in a chromatin context, we analyzed the chromatin structure of the GM-CSF gene in T cells and the role of NF-κB proteins in chromatin remodeling. We show here that chromatin remodeling occurs across a region of the GM-CSF gene between −174 and +24 upon T cell activation, suggesting that remodeling is limited to a single nucleosome encompassing the proximal promoter. Nuclear NF-κB levels appear to play a critical role in this process. In addition, using an immobilized template assay we found that the ATPase component of the SWI/SNF chromatin remodeling complex, brg1, is recruited to the GM-CSF proximal promoter in an NF-κB–dependent manner in vitro. These results suggest that chromatin remodeling across the GM-CSF promoter in T cells is a result of recruitment of SWI/SNF type remodeling complexes by NF-κB proteins binding to the CD28 response region of the promoter
Determinants of a transcriptionally competent environment at the GM-CSF promoter
Granulocyte macrophage-colony stimulating factor
(GM-CSF) is produced by T cells, but not B cells,
in response to immune signals. GM-CSF gene
activation in response to T-cell stimulation requires
remodelling of chromatin associated with the
gene promoter, and these changes do not occur in
B cells. While the CpG methylation status of the
murine GM-CSF promoter shows no correlation with
the ability of the gene to respond to activation, we
find that the basal chromatin environment of the
gene promoter influences its ability to respond to
immune signals. In unstimulated T cells but not B
cells, the GM-CSF promoter is selectively marked
by enrichment of histone acetylation, and association
of the chromatin-remodelling protein BRG1.
BRG1 is removed from the promoter upon activation
concomitant with histone depletion and BRG1
is required for efficient chromatin remodelling and
transcription. Increasing histone acetylation at
the promoter in T cells is paralleled by increased
BRG1 recruitment, resulting in more rapid chromatin
remodelling, and an associated increase in GM-CSF
mRNA levels. Furthermore, increasing histone
acetylation in B cells removes the block in chromatin
remodelling and transcriptional activation
of the GM-CSF gene. These data are consistent
with a model in which histone hyperacetylation
and BRG1 enrichment at the GM-CSF promoter,
generate a chromatin environment competent
to respond to immune signals resulting in gene
activation
GM-CSF promoter chromatin remodelling and gene transcription display distinct signal and transcription factor requirements
GM-CSF promoter chromatin remodelling and gene transcription display distinct signal and transcription factor requirements
Granulocyte-macrophage colony stimulating factor (GM-CSF) plays a key role in myeloid cell function and is rapidly and transiently expressed in T cells in response to immune or inflammatory stimuli. Induction of GM-CSF gene expression is accompanied by changes in chromatin structure across the proximal promoter region of the gene. We show that the promoter remodelling and subsequent gene transcription occurs with distinct signal and transcription factor requirements. Activation of the protein kinase C (PKC) signalling pathway is sufficient to induce changes in chromatin structure across the promoter, but both the PKC and calcium signalling pathways are required for efficient gene transcription. Although NFAT transcription factors contribute to GM-CSF gene transcription, they are not required for promoter remodelling. However, the presence of the nuclear factor-κB transcription factor, c-Rel, in the nucleus is strongly correlated with and required for the events of chromatin remodelling
Chromatin remodeling and transcriptional regulation of cytokine gene expression in T cells
Chromatin Remodelling: Distinct Molecular Events During Differentiation and Activation of T Cells
T lymphocytes undergo a complex series of developmental events in the thymus to become mature but naïve circulating T cells. These naïve T cells are activated during the response to pathogens to produce immune mediators and undergo further differentiat
Functional interaction between the HIV transactivator Tat and the transcriptional coactivator PC4 in T cells
The human immunodeficiency virus (HIV) transactivator Tat is a potent activator of transcription from the HIV long terminal repeat and is essential for efficient viral gene expression and replication. Tat has been shown to interact with components of th