TLR-LNCRNAS · Systematic elucidation of the regulatory roles of large non-coding RNAs in the toll-like receptor pathway

Dendritic cells (DCs) are a critical component of the innate immune system, as they play a major role in pathogen-sensing, initiation of inflammatory reactions, and activation of cells of the adaptive immune system. DCs express several isoforms of the toll-like receptor (TLR) family and other pattern recognition receptors that interact with molecular structures conserved among many microbial species. These interactions initiate a pathogen-specific tailored signaling- transcriptional response, which activates thousands of genes necessary to alert the adaptive immune system and eliminate the pathogenic threat. One of the key questions is how are these gene programs generated and regulated?Eukaryotic genomes transcribe several types of RNA molecules, ranging from protein-coding mRNA molecules to short non-coding transcripts. Large non-coding RNA (lncRNA) molecules are probably the least studied of all RNA species, and for a long time were considered to be “transcriptional noise”. Recent studies highlight the importance of lncRNA in multiple physiological and pathological responses ranging from embryonic stem cell function to cancer.In this study we would like to investigate the role of lncRNAs and chromatin regulators in coordinating a genetic network that directs the observed dynamic output of TLR-activated pathways. We will use high throughput methods to measure the expression of lncRNA in dendritic cells, activated by pathogen components. We will validate the functional roles of these lncRNA using RNAi and asses their mechanistic role in the TLR pathway by elucidating the physical association between these lncRNAs and chromatin regulators. This will allow us to illuminate the roles lncRNAs play in pathogen sensing in mammals.