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Dynamics of enhancers in myeloid antigen presenting cells upon LPS stimulation.

ABSTRACT: BACKGROUND: Recent studies have underscored the role of enhancers in defining cell type-specific transcriptomes. Cell type-specific enhancers are bound by combinations of shared and cell type-specific transcription factors (TFs). However, little is known about combinatorial binding of TFs to enhancers, dynamics of TF binding following stimulation, or the downstream effects on gene expression. Here, we address these questions in two types of myeloid antigen presenting cells (APCs), macrophages and dendritic cells (DCs), before and after stimulation with lipopolysaccharide (LPS), a potent stimulator of the innate immune response. RESULTS: We classified enhancers according to the combination of TFs binding them. There were significant correlations between the sets of TFs bound to enhancers prior to stimulation and expression changes of nearby genes after stimulation. Importantly, a set of enhancers pre-bound by PU.1, C/EBP?, ATF3, IRF4, and JunB was strongly associated with induced genes and binding by stimulus-activated regulators. Our classification suggests that transient loss of ATF3 binding to a subset of these enhancers is important for regulation of early-induced genes. Changes in TF-enhancer binding after stimulation were correlated with binding by additional activated TFs and with the presence of proximally located enhancers. CONCLUSIONS: The results presented in this study reveal the complexity and dynamics of TF- enhancer binding before and after stimulation in myeloid APCs.

SUBMITTER: Vandenbon A

PROVIDER: S-EPMC4304210 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Dynamics of enhancers in myeloid antigen presenting cells upon LPS stimulation.

Vandenbon Alexis A Teraguchi Shunsuke S Takeuchi Osamu O Suzuki Yutaka Y Standley Daron M DM

BMC genomics 20141212

<h4>Background</h4>Recent studies have underscored the role of enhancers in defining cell type-specific transcriptomes. Cell type-specific enhancers are bound by combinations of shared and cell type-specific transcription factors (TFs). However, little is known about combinatorial binding of TFs to enhancers, dynamics of TF binding following stimulation, or the downstream effects on gene expression. Here, we address these questions in two types of myeloid antigen presenting cells (APCs), macroph ...[more]

PMID: 25560382

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Project description:Myeloid-derived suppressor cells (MDSC) and M2 monocytes/macrophages are two types of suppressive myeloid antigen presenting cells that have been shown to promote tumor progression and correlate with poor prognosis in cancer patients. Tumor antigen specific monoclonal antibodies (mAb) have emerged as important agents for cancer therapy. In addition to the direct inhibition of tumor growth, the Fc portions of the therapeutic mAbs, such as the IgG1 portion of the anti-epidermal growth factor receptor (EGFR) mAb cetuximab, might interact with the Fc-gamma receptors (Fc?R) on myeloid cells and modulate their suppressive activity.Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) on the UPCI 08-013 NCT01218048 trial were treated with single-agent cetuximab before surgery. Blood were collected pre- and post-cetuximab treatment to analyze frequency of monocytic MDSC (CD11b(+)CD14(+)HLA-DR(lo/-)), granulocytic MDSC (LIN(-)CD11b(+)CD15(+)) and CD11b(+)CD14(+)HLA-DR(hi) monocytes by flow cytometry. Besides, CD11b(+)CD14(+)HLA-DR(hi) monocytes were sorted for qPCR analysis of IL-10 and IL-12B transcripts. MDSC were generated in vitro with or without coated hIgG1 and tested for suppressive activity in mixed leukocyte reaction (MLR). Naïve monocytes from HNSCC patients co-cultured with tumor cell lines in the presence of cetuximab or hIgG1 were analyzed for M1/2 surface markers and cytokines.We observed significantly increased monocytic MDSC in non-responders and decreased granulocytic MDSC in responders after cetuximab treatment. In addition, circulating CD11b(+)CD14(+)HLA-DR(hi) monocytes of cetuximab responders displayed attenuated M2 polarization, with decreased CD163(+) expression and IL-10 transcripts after cetuximab treatment. This beneficial effect appeared to be Fc?R dependent, since CD16 ligation reproduced the reversal of suppressive activity of MDSC in vitro. CD14(+) naïve monocytes from the co-cultures of tumor cells, cetuximab and HNSCC patient PBMC or purified monocytes were skewed to an M1-like phenotype, with increased expression of HLA-DR, CD86 and production of IL-12 p70. Likewise, reduced M2 features (expression of CD163 and production of IL-10) were found after crosslinking CD16 on the surface of monocytes to cetuximab-coated tumor cells.Our studies demonstrate a novel function of cetuximab in ameliorating suppressive phenotypes of Fc?R bearing myeloid cells in cancer patients, which is associated with better clinical outcome of cetuximab-treated patients.#NCT01218048. Registered 7 October 2010.

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Dynamics of enhancers in myeloid antigen presenting cells upon LPS stimulation.

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Dynamics of enhancers in myeloid antigen presenting cells upon LPS stimulation.

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