The NF-B family of transcription factors are stress sensors in a wide variety of cell types. Their nuclear expression can be induced in response to diverse stimuli including reactive oxygen species (ROS), DNA damage, endoplasmic reticulum (ER) stress, and inflammatory cytokines such as TNF and IL-1. NF-B target genes include inflammatory cytokines such as IL-6, TNF and IL-1, cell adhesion molecules, and molecules involved in maintenance of cell viability. The fundamental goal of our studies is to identify molecular mechanisms that underlie cell-specificity and stimulus-specificity of NF-B-dependent gene expression. In some cell systems NF-B has been shown to intersect with functions of the general transcription factor GTFIIi. Thus, in parallel, we explore the role of GTFIIi-driven transcription in B and T lymphocytes. During FY19: 1)We carried out ChIP-Seq with anti-RelA and anti-Rel antibodies in spleen B cells activated via the B cell antigen receptor for varying time periods. We found that RelA was recruited to the genome at early time points (1h) after activation, whereas Rel was recruited at longer time points (18h). Interestingly, though these two proteins have closely related DNA binding specificities, more than 60% of binding sites were unique for each protein. Thus, mechanisms other than target DNA specificity must control specificity of RelA or Rel binding to the genome. 2)We carried out ChIP-Seq experiments with anti-RelB antibodies in WT and NFKB2-deficient MEFs activated by TNF. We found that RelB gained features of classical NF-B responsiveness in the absence of NFKB2. 3)ATAC-Seq and RNA-Seq studies were completed in GTFIIi-deficient B cells. Computational analyses are ongoing. We have bred floxed alleles of GTFIIi to CD4-cre to generate GTFIIi-deficient T cells. Gene expression and epigenetic studies are ongoing.
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| Kaileh, Mary; Vazquez, Estefania; MacFarlane 4th, Alexander W et al. (2016) mTOR-Dependent and Independent Survival Signaling by PI3K in B Lymphocytes. PLoS One 11:e0146955 |
| Fowler, Trent; Garruss, Alexander S; Ghosh, Amalendu et al. (2015) Divergence of transcriptional landscape occurs early in B cell activation. Epigenetics Chromatin 8:20 |
| Maul, Robert W; Cao, Zheng; Venkataraman, Lakshmi et al. (2014) Spt5 accumulation at variable genes distinguishes somatic hypermutation in germinal center B cells from ex vivo-activated cells. J Exp Med 211:2297-306 |
| Kaileh, Mary; Sen, Ranjan (2012) NF-ýýB function in B lymphocytes. Immunol Rev 246:254-71 |
| Olkhanud, Purevdorj B; Damdinsuren, Bazarragchaa; Bodogai, Monica et al. (2011) Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4? T cells to T-regulatory cells. Cancer Res 71:3505-15 |
| Fowler, Trent; Sen, Ranjan; Roy, Ananda L (2011) Regulation of primary response genes. Mol Cell 44:348-60 |
| Sen, Ranjan (2011) The origins of NF-?B. Nat Immunol 12:686-8 |
| Damdinsuren, Bazarragchaa; Zhang, Yongqing; Khalil, Ashraf et al. (2010) Single round of antigen receptor signaling programs naive B cells to receive T cell help. Immunity 32:355-66 |
| Sen, Ranjan; Smale, Stephen T (2010) Selectivity of the NF-{kappa}B response. Cold Spring Harb Perspect Biol 2:a000257 |
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