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

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

Immune cells play an essential role in protecting the body from invading pathogens by directing pathogen specific responses. These pathogen-tailored responses are executed largely through the induction of specific gene programs. Recent studies suggest that deregulation of specific gene modules in the toll-like receptor (TLR) pathway affect diverse set of diseases including diabetes, inflammatory bowl disease, lupus and rheumatoid arthritis. While upstream signaling components that mediate pathogen-sensing by TLRs, can explain broad differences in the responses to distinct TLRs, relatively little is known about the downstream transcriptional cascades that directly control the specific gene expression. There is currently great need to comprehend the molecular mechanisms of how these dynamic gene responses are controlled. Recent advances in high-throughput genomic technologies provide an extraordinary opportunity to develop and apply systematic approaches to comprehensively identify the molecular mechanisms by which these programs are regulated. In recent work, we used novel unbiased approaches, to systematically measure the regulatory role of transcriptional regulators involved in the response to TLR activation. These approaches enabled the discovery of a complex circuit of over 100 functional regulators that affect the transcriptional output. Recently, We demonstrated that 1. The mammalian genome contains much more then anticipated functional large non-coding RNA (lncRNA), 2. Subsets of these lncRNA are regulated in innate immune cells by pathogen stimuli 3. lncRNA are associated with and regulate chromatin complexes. Our premise in this proposal is that lncRNA play a major role in regulating gene expression programs and immune outcome. Here, we propose to systematically uncover the regulatory circuits of lncRNA controlling the transcriptional response of primary dendritic cells (DC) to pathogens. For this end, through out the proposal we have developed single cell RNA-Seq (Jaitin et al, Science 2014; Paul et al, Cell 2015; Matcovitch et al, Science 2016; Gury et al, Cell 2016, Jaitin et al Cell 2016) and ChIP-Seq (Lara et al Science 2014, Borensten et al Molecular Cell 2014; Weiner et al Nature Biotechnology 2016) to identify regulatory regions and large non coding RNA involved pathogen exposure and elucidate their regulation. Our studies had a significant impact on how we understand how hematopoiesis and immune responses are coded in our genomes. Specifically, this study enabled us to identify the protein coding genes and regulatory sequences in the genome and how they control blood cell development and immune function. To this end, we developed novel single-cell genomic technologies and combine them with models for hematopoiesis and immune response, computation, high-throughput sequencing and genome engineering methods. Collectively, these approaches enabled us to gain deep insights into diverse regulatory mechanisms underlying hematopoietic development and immune decisions. The advanced tools we have developed for in vivo genome engineering, single-cell RNA-Seq and epigenetic analysis place us in a unique position to decipher novel pathways for immune checkpoints involved in pathologies ranging from cancer to neurological, hematopoiesis-related diseases and diabetes. Our premise is that these systematic studies will bridge the gap between basic regulatory mechanisms and their physiological in vivo consequences in human diseases. With the help of the CIG integration grant, Since its establishment in 2011, my lab at the Weizmann Institute has been consistently successful in producing high-impact discoveries and seminal contributions in the fields of genomics, hematopoiesis and immunity by applying novel single-cell genomic technologies. These include the first systematic measurements of chromatin dynamics across development and tissues (Lara et al, Science 2014; Lavin et al, Cell 2014; Borenstein et al, Molecular Cell 2014; Garber et al Molecular Cell 2013) and single-cell genomic studies of hematopoietic progenitors and immune heterogeneity (Jaitin et al, Science 2014; Paul et al Cell 2015; Matcovitch et al Science 2016; Jaitin et al Cell 2016). We frequently contribute reviews in leading journals, and I have given numerous invited talks and organized leading conferences in the fields of immunology, and genomics, including the last four years of the major single-cell genomics meeting. These outstanding contributions to the life sciences were recognized by a number of prestigious prizes, including the EMBO Gold Medal award.

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