NF-kB activation and function in B lymphocytes

National Institute On Aging

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Abstract

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 FY21 we accomplished the following: - Combined time-dependent ChIP-Seq, ATAC-Seq, RNA-Seq and scRNA-Seq studies in WT, RelA-cKO and Rel-KO B cells were compiled into a manuscript that will be submitted for publication befo0re end pf FY21. These studies identified many novel targets of NF-kB in BCR-activated B cells as well defined a cascade of gene expression initiated by NF-kB activation. Many of the newly identified NF-kB target genes provide insight in to subunit-specific functions of RelA and Rel in B cell biology, including germinal center responses and cancer. - carried out time-dependent RelA ChIP-Seq in BV2 (microglial) cells to identify RelA targets in response to LPS activation. Sensitivity to NF-kB induction was assessed by including the IKK2 inhibitor BAY-11-7082 in RNA-Seq studies. These studies were designed to address cell-specific mechanisms of NF-kB-dependent gene expression by comparing responses of B cells to an innate cell type. - initiated studies to identify RelA and Rel target genes in human and mouse B cell lymphomas.