More than 98% of the human genome is non-coding, generating a wide 14variety of long non-coding RNAs (lncRNAs) depending on cell type. The biological function of most lncRNAs is currently not well defined and their systematic annotation is challenging due to their low expression, rapid degrada-tion, high cell type-specificity, poor conservation across organisms, and lack of families of functionally orthologous lncRNAs. As most genetic variants associ-ated with disease are located in non-coding regions, characterizing the function of lncRNAs is of fundamental importance for understanding human disease.As lncRNAs are enriched in the cell nucleus, they may have regulatory func-tions by acting directly on chromatin. We analyzed the 3D structure of chro-matin in the nucleus using Hi-C, which captures pairs of DNA segments close to each other in 3D space and characterized each lncRNA by the functional categories of protein-coding genes in its vicinity. Functional annotations of 13,534 lncRNAs, generated by our analysis in 18 different cell types and tissues, were disseminated publicly using ZENBU, an integrated visualization and data analysis system.Complementary to these sequencing-based strategies, we are developing im-aging methods for electron microscopy to visualize chromosome conformation at nanometer-scale resolution and to landmark specific genomic regions such as promoters and enhancers, as well as other biomolecules, in these images. Our long-term aim is to understand the structure of chromatin as the biophysi-cal basis of gene regulation in the nucleus.In response to the ongoing SARS-CoV-2 pandemic, we collaborate with multiple laboratories in our Center to better understand the response of human cells to infection by different strains of the virus by analyzing and comparing the transcriptome following infection.Figure: Electron microscope image of MCF-10A human mam-mary epithelial cells (in collaboration with the IMS Laboratory for Cellular Epigenomics, the IMS Laboratory for Skin Homeostasis and Tokyo University of Technol-ogy). Chromatin was stained with osmium and can be observed in the electron micrographs as dark areas. The scale bars correspond to 2 μm (left) and 500 nm (right).Recent Major PublicationsHashimoto M, Saito Y, Nakagawa R, Ogahara I, Takagi S, Takata S, Amitani H, Endo M, Yuki H, Ramilowski JA, Sev-erin J, Manabe R, Watanabe T, Ozaki K, Kaneko A, Kajita H, Fujiki S, Sato K, Honma T, Uchida N, Fukami T, Okazaki Y, Ohara O, Shultz LD, Yamada M, Taniguchi S, Vyas P, De Hoon M, Momozawa Y, Ishikawa F. Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia. Nat Cancer 2, 340-356 (2021)Ramilowski JA, Yip CW, Agrawal S, Chang JC, Ciani Y, Kulakovskiy IV, Mendez M, Ooi JLC, Ouyang JF, Parkinson N, Petri A, Roos L, Severin J, Yasuzawa K, Abugessaisa I, Akalin A, Antonov IV, Arner E, Bonetti A, Bono H, Borsari B, Brombacher F, Cameron CJ, Cannistraci CV, Cardenas R, Cardon M, Chang H, Dostie J, Ducoli L, Favorov A, Fort A, Garrido D, Gil N, Gimenez J, Guler R, Handoko L, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto K, Hayatsu N, Heutink P, Hirose T, Imada EL, Itoh M, Kacz-kowski B, Kanhere A, ..., De Hoon M, Shin JW, Carninci P. Functional annotation of human long noncoding RNAs via molecular phenotyping. Genome Res 30, 1060-1072 (2020)Alam T, Agrawal S, Severin J, Young RS, Andersson R, Arner E, Hasegawa A, Lizio M, Ramilowski JA, Abuges-saisa I, Ishizu Y, Noma S, Tarui H, Taylor MS, Lassmann T, Itoh M, Kasukawa T, Kawaji H, Marchionni L, Sheng G, Forrest ARR, Khachigian LM, Hayashizaki Y, Carninci P, De Hoon MJL. Comparative transcriptomics of primary cells in vertebrates. Genome Res 30, 951-961 (2020)Laboratory for Applied Computational GenomicsTeam Leader: Michiel de Hoon
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