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    • MK 886 australia HMGA proteins have also been linked to loca

    2023-12-04

    HMGA proteins have also been linked to localized changes in chromatin/nucleosome structure and alterations of cellular phenotype during induction of gene transcription in activated T lymphocytes. An adaptive immune response is initiated when naïve resting T lymphocytes encounter their corresponding antigen on the surface of antigen-presenting cells that also express co-stimulatory molecules. As a result of such interactions, T cells become activated and undergo marked phenotypic changes termed blast formation, a process that is critically regulated by the coordinate expression of cytokine genes. A key event in the initial activation of T cells is the production of the cytokine IL-2 and its high affinity receptor (IL-2R) which is comprised of α, β and γ subunits [60]. Together IL-2 and IL-2R form a strong autocrine stimulatory loop for promoting T cell growth and clonal expansion. IL-2 also contributes to B cell differentiation and stimulates both macrophage and NK cell activation [151]. HMGA1 has been demonstrated to participate in the transcriptional activation of both the IL-2 [9,69,70] and IL-2α [76,76,77] genes in activated lymphoid cells. Furthermore, during the activation of both genes, HMGA1 has been implicated in the “remodeling” or removal of inhibitory nucleosomes which, in unstimulated T cells, are positioned on the recognition sites of key regulatory factors that are required for transcription initiation. Similar to induction of IFN-β, transcriptional activation of IL2-Rα is regulated by enhanceosome formation involving the interaction of HMGA1 with other transcription factors (Elf-1, STAT5, GATA, etc.) and several positive regulatory regions (e.g., PRRI, PRRII and PRRIII) in the gene's proximal promoter [76,77]. However, in contrast to the promoter of IFN-β, which in uninfected cells has two positioned nucleosomes flanking naked DNA where the enhanceosome forms, the promoter of the IL-2Rα in resting T cells has a strongly positioned nucleosome that encompasses one of the positive regulatory regions (i.e., PRRII), the site where an enhanceosome is assembled. The PRRII region contains two stretches of A/T-rich DNA, potential MK 886 australia for HMGA1, one of which partially overlaps the recognition sequence for Elf-1, a transcription factor that is required for both enhanceosome formation and IL-2Rα gene activation in vivo. Following T cell activation, the inhibitory nucleosome on the PRRII region is removed/remodeled, enhanceosome assembly ensues and transcription is initiated [137]. Chromatin reconstitution experiments employing IL-2Rα DNA have demonstrated that a nucleosome is assembled on the PRRII region in vitro at the same position as the one found in vivo. In this reconstituted nucleosome, the A/T-rich stretch that overlaps the Elf-1 site is situated on the surface of the core particle and the second A/T-rich stretch is located in the linker region immediately 5′ upstream of the nucleosome [137]. In vitro experiments using recombinant proteins showed that HMGA1, but not Elf-1, is able to bind the A/T-stretch on the surface of the nucleosome as well as to the stretch located in the adjacent linker region. Importantly, it was found that two different HMGA1 protein molecules bound to the two separate A/T-rich stretches in a direction-specific, “tail-to-tail” manner in vitro. If this in vitro pattern of HMGA1 binding likewise occurs in vivo, it could potentially impart a unique identifying “marker” or fingerprint to the positioned PRRII nucleosome that distinguishes it from all of the other core particles in the cell [137]. Based on these observations, and the fact that HMGA1 protein is present at only very low levels in resting lymphocytes but is rapidly induced in T cells following stimulation [64], a model for activation of the IL-2Rα promoter has been proposed [135]. In this model, HMGA proteins are actively involved in both the initial disruption of the PRRII nucleosome (likely mediated via direct binding to the core particle and recruitment of remodeling factors) and in the subsequent formation of an enhanceosome on this same region of promoter DNA. The dual ability of HMGA proteins to bind to A/T-rich DNA sequences on the surface of nucleosome particles [137,141] and to also participate in enhanceosome formation makes it reasonable to expect that a similar activation scenario applies to other inducible genes whose promoters contain positioned nucleosomes and whose expression is controlled by HMGA proteins (e.g., the human IL-2 cytokine gene [9,69,70]).