The body-wide transcriptome is generated by the spatiotemporal orchestra-18Enhancer RNAPromoterCell-type specific EnhancerDisease-SNPsAltering gene expressionNET-CAGECAGEtion of cis-regulatory DNA elements such as promoters and enhancers. In particular, enhancers are distal cis-regulatory elements that are crucial for the establishment of cell type-specific function and identity in health and disease. We aim to decipher the cis-regulatory code that governs the transcriptional landscapes of malignancies, thereby gaining fundamental insight into cancer development and maintenance.To investigate the cis-regulatory code, we developed a new method, native elongating transcript-cap analysis of gene expression (NET-CAGE), to deter-mine globally the 5’ ends (or transcription start sites) of nascent RNAs. This method permits sensitive detection of even unstable transcripts, including en-hancer-derived RNAs. Thus, NET-CAGE enabled ultra-sensitive detection of a number of enhancers at nucleotide resolution as well as the genes that are regu-lated by them (Hirabayashi et al. Nature Genetics, 2019). More recently, we have developed a new 5’ single-cell RNA sequencing (5’ scRNA-seq) approach to investigate functional enhancers from heterogeneous cell types within a given tissue/cell (Oguchi et al., Manuscript submitted). We believe in the importance of developing original disruptive technologies that can define paradigms and resolve otherwise unsolvable problems in biomedicine.We are applying our new methods such as NET-CAGE and 5’ scRNA-seq to describe the active cis-regulatory landscape across hundreds to thousands of human samples including various types of tumors and immune cells, to com-prehensively catalog cell-type specific enhancers, genes and long non-coding RNAs. Furthermore, by integrating large-scale human disease genomics data with clinical information, we study disease-relevant genetic elements that can be exploited to develop novel molecular therapeutic targets and predictive bio-markers. Our ultimate long-term goal is to revolutionize drug discovery, medi-cine and healthcare.Figure: Building an atlas of transcribed enhanc-ers across the human body for decoding human diseasesEnhancers are small segments of DNA, cis-regulatory elements that significantly enhance the expression of target genes and play key roles in the establishment of cell-type-specific function and identity. Single nucleotide polymorphisms associated with human diseases (GWAS-SNPs) are highly enriched in enhancer regions and are thought to alter disease susceptibility by changing the expression levels of target genes. We have developed original methods such as NET-CAGE to detect enhancer RNAs transcribed from active enhancers with high sensitivity, and are studying the relationship between enhancers and human diseases.Recent Major PublicationsKojima S, Koyama S, Ka M, Saito Y, Parrish EH, Endo M, Takata S, Mizukoshi M, Hikino K, Takeda A, Fujii A, Heaton S, Koide R, Kamada JA, Noguchi M, Hamada M, Kamatani Y, Murakawa Y, Ishigaki K, Nakamura Y, Ito K, Terao C, Momozawa Y, Parrish NF. Mobile elements in human population-specific genome and phenotype divergence. Nature Genetics 55(6):939-951 (2023)Najnin RA, Al Mahmud MR, Rahman MM, Takeda S, Sasanuma H, Tanaka H, Murakawa Y, Shimizu N, Akter S, Takagi M, Sunada T, Akamatsu S, He G, Itou J, Toi M, Miyaji M, Tsutsui KM, Keeney S, Yamada S. ATM sup-presses c-Myc overexpression in the mammary epitheli-um in response to estrogen. Cell Reports 42(1):111909. (2023)Koido M, Hon CC, Koyama S, Kawaji H, Murakawa Y, Ishigaki K, Ito K, Sese J, Parrish NF, Kamatani Y, Carninci P, Terao C. Prediction of the cell-type-specific transcrip-tion of non-coding RNAs from genome sequences via machine learning. Nature Biomedical Engineering 7(6):830-844 (2023)Invited presentationsMurakawa Y. “Deciphering the enhancer code using 5’ single-cell RNA sequencing” 82nd Annual Meeting of the Japanese Cancer Association (Yokohama, Japan) September, 2023Murakawa Y. “An atlas of transcribed enhancers across immune cell diversity for decoding human immune-mediated diseases” 2nd International Symposium of Clinical Immunology (Kamakura, Japan) May, 2023Murakawa Y. “Development of genome analysis technol-ogy to elucidate the function of the human genome” 36th International Mammalian Genome Conference (Tsukuba, Japan) March, 2023RIKEN-IFOM Joint Laboratory for Cancer GenomicsTeam Leader: Yasuhiro Murakawa
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