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 FY22 we accomplished the following: We applied the 3-pronged approach developed in our section to identify NF-kB target genes in murine primary B lymphocytes activated via the B cell antigen receptor (BCR). We had previously shown that BCR stimulation activates two phases of NF-kB. A rapid and transient phase that is comprised of both RelA and Rel and a persistent late phase that is dominated by Rel. Accordingly, we carried out time-dependent RelA and Rel chromatin immunoprecipitation sequencing (ChIP-Seq) and gene expression responses in wild type, RelA-deficient, Rel-deficient and doubly deficient B cells. We identified many new Rel target genes that provided insights into the role of this NF-kB family member in germinal center responses and lymphomagenesis. A manuscript describing these studies was submitted for publication and is currently being revised for re-submission. We completed a study on the role of role transcription factor TFII-I in murine B cells. Loss of Gtf2i, the gene encoding TFII-I, in B cells resulted in changed transcriptome and chromatin landscape that had features of myeloid cells. These changes coincided with enhanced sensitivity to lipopolysaccharide (LPS) and TFII-I-deficient B cells showed increased switching to IgG3 in vitro. These observations demonstrate a role for TFII-I in maintaining immune homeostasis and provide mechanistic clues for GTF2I polymorphisms associated with B cell dominated autoimmune diseases in humans.