A New crucial role for complement receptor CD46 in chromatin packaging and direct gene regulation

Abstract

Abstract Chromatin is the condensed form of DNA ‘packaged’ by positively charged histones in the nucleus. Post-translational modifications of histones regulate nucleosome dynamics, chromatin accessibility and gene expression. Signals mediated by autocrine activation of the human-specific complement regulator/receptor CD46 during T cell receptor stimulation are vital to Th1 induction in CD4+ T cells. CD46 is expressed in different isoforms that arise through alternative-splicing of a single gene - with two distinct cytoplasmic tails: CYT-1 or CYT-2. CYT-1 nuclear translocation is critical for the expression of genes that are involved in the metabolic adaptations underlying Th1 activity. Because CD46-CYT-1 lacks direct DNA-binding domains, we hypothesized that CYT-1 interacts with transcription factor (TF) activator and/or repressor complexes to control gene expression. ChIP-seq analyses of human CD4+ T cells using anti-CYT-1 antibody revealed 327 genes as direct CD46-CYT-1 targets and five conserved TF-binding motifs allowing us to define CYT-1-interacting TFs in T cells. Interestingly, pathway analysis of CYT-1-regulated genes identified broad nucleosome regulation as top ‘CYT-1 activity’. Indeed, we confirmed that CYT-1 directly regulates the expression and post-translational modification of core histones including H3 and H4 at lysine (4, 8, 9, 12, 20 and 27) in a time-dependent manner. Such CD46-driven nucleosome regulation was aberrant in T cells from CD46-deficient patients, explaining now mechanistically their inability to mount Th1 responses. These data define a novel role for CD46 in chromatin packaging and support our notion that intracellular/autocrine complement regulates basic cell-physiological processes.