Epigenomics of conventional type-I dendritic cells depicted preferential control of TLR9 versus TLR3 response by NCoR1 through differential IRF3 activation

Abstract

Tight control of gene regulation in dendritic cells (DCs) is important to mount pathogen specific immune responses. Apart from transcription factor binding, dynamic regulation of enhancer activity through global transcriptional repressors like Nuclear Receptor Co-repressor 1 (NCoR1) plays a major role in fine-tuning of DC responses. However, how NCoR1 regulates enhancer activity and gene expression in individual or multiple Toll-like receptor (TLR) activation in DCs is largely unknown. In this study, we did a comprehensive epigenomic analysis of murine conventional type-I DCs (cDC1) across different TLR ligation conditions. We profiled gene expression changes along with H3K27ac active enhancers and NCoR1 binding in the TLR9, TLR3 and combined TLR9 + TLR3 activated cDC1. We observed spatio-temporal activity of TLR9 and TLR3 specific enhancers regulating signal specific target genes. Interestingly, we found that NCoR1 differentially controls the TLR9 and TLR3-specific responses. NCoR1 depletion specifically enhanced TLR9 responses as evident from increased enhancer activity as well as TLR9-specific gene expression, whereas TLR3-mediated antiviral response genes were negatively regulated. We validated that NCoR1 KD cDC1 showed significantly decreased TLR3 specific antiviral responses through decreased IRF3 activation. In addition, decreased IRF3 binding was observed at selected ISGs leading to their decreased expression upon NCoR1 depletion. Consequently, the NCoR1 depleted cDC1 showed reduced Sendai Virus (SeV) clearance and cytotoxic potential of CD8+ T cells upon TLR3 activation. NCoR1 directly controls the majority of these TLR specific enhancer activity and the gene expression. Overall, for the first time, we revealed NCoR1 mediates transcriptional control towards TLR9 as compared to TLR3 in cDC1. Graphical abstract

NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation

“…The preferential implication of NCoR1 is also being established in energy metabolism with respect to autophagy and atherosclerosis [ [28] , [29] , [30] ]. In the context of regulation of inflammatory versus tolerogenic immune response, our earlier functional and epigenomics studies on type I conventional DCs have demonstrated that NCoR1 depletion polarizes DCs towards tolerance that in turn shifts the balance of naive CD4 + co-cultured T cells towards Tregs [ 31 , 32 ]. However, the metabolic adjustments of these tolerogenic DCs is largely unknown, hence, in this study we focused to understand the control of various metabolic pathways required to maintain a fine balance of inflammation and tolerance in pursuit of energy metabolism in both murine and human DCs.…”

The Potential of Dendritic Cell Subsets in the Development of Personalized Immunotherapy for Cancer Treatment

“…cDC1s are also specialized in activating CD8 + naive T-cells through cross-presentation via MHC I molecules, playing a crucial role in anti-tumor and antiviral immune responses [24,28]. The presence of Toll-like receptor 3 (TLR3), an endosomal protein, is characteristic of cDC1s, and it is necessary for the recognition of double-stranded RNA, an intermediate in the replication of many viruses [29].…”