68a)a)c)d)b)c)b)aiming to create a comprehensive molecular reference map of human cells as a basis for understanding human health and diseases. At RIKEN IMS, led by Drs. Piero Carninci, Jay Shin and Chung-Chau Hon, we contribute to the HCA by coordinating its activities among Asian institutions (e.g. Asia-HCA meetings), developing single-cell experimental and computational methods (e.g. single-cell 5’ RNA-Seq analysis methods) and generating single-cell molecular atlases from Asian samples (e.g. Asian Im-mune Diversity Atlas (AIDA)). Specifically, we have constructed a transcribed cis-regulatory elements (tCRE) atlas using single-cell 5’ RNA-seq, capturing over 340,000 single-cells from 23 human tissues and annotating more than 175,000 tCREs, substantially program with Keio University School of Medicine, “Keio-RIKEN IMS Human Biology and Medicine Program (HuMED)”, aiming to maximize the social benefits of medical knowledge derived from genomic studies. The creation of a Keio-RIKEN IMS joint laboratory on the Keio Shinanomachi campus, led by Drs. Jay Shin and Chung-Chau Hon, strengthens the already well-established medical research at Keio University with the advanced genomic technologies from RIKEN IMS, through collaborative projects over the next decade. The HuMED project focuses on the application of single-cell genomics to medical research, in particular large-scale studies of diseases cohorts at single cell resolution. Notable examples include profiling of colon biopsies from an ulcerative colitis and Crohn’s disease cohort (n=300), enhancing the scope and granularity of existing CRE annotations in the human genome. This atlas unveils patterns of gene regula-tion, revealing connections between broadly expressed promot-ers and cell type-specific distal tCREs (Figure). Assessing trait heritability at single-cell resolution with a novel tCRE module-based approach, we uncovered the nuanced trait-gene regulatory relationships across a continuum of cell populations. This analysis framework was also extended to the AIDA project, which aims to characterize the extent of variation in >1.5 million immune cells from 700 individuals collected from eight Asian countries. In summary, these HCA activities leveraged the expertise in single-cell transcriptomics and medical genetics at RIKEN IMS to fur-ther our understanding of the cellular contexts of human diseases.iPSC induced motor neurons from an ALS cohort (n=150), and salivary gland biopsies from a Sjögren’s syndrome cohort (n=30). In addition, the joint program also includes 10+ other projects including colon transplantation, spatial transcriptomics of brains of Alzheimer’s disease and Schizophrenia disease patients, skin biopsies of atopic dermatitis patients, characterization of human gut T cell populations, in vitro differentiation of neural lineages, etc. One of the highlights has been the identification of a cytotox-ic CD4+CD8A+ T cell subset in the human gut and its similarity to mouse CD4 cytotoxic T cells (Figure). The joint research lab is a hub for fruitful collaborations between RIKEN IMS and Keio University, generating highly informative genomic data to trans-form medicine for a brighter future.Figure: A single-cell atlas of transcribed cis-regula-tory elements in the human genomea) Single-cell (small points) and meta-cell (large points) UMAP colored by Level 1 (Lv1) cell type clustering, meta-cells are positioned by the average UMAP positions of their single-cells, #meta-cells and average cells per meta-cell shown for each Lv1 cluster. b) Alternative promoter usage by IL1RN. An asterisk represents significant alternative promoter usage (p < 0.05, Wilcoxon test). c) Alternative distal tCRE at BCL2A1. An asterisk represents significant alternative D-tCRE usage (p < 0.05, Wilcoxon test). Distal tCREs were linked to target promoters by chromatin interaction and co-activity data.Figure: Identification of a cytotoxic CD4+CD8A+ T cell subset in human gut and its similarity to mouse CD4 cytotoxic T cellsa) Sorting strategy for the human single-cell RNA-seq data: Lamina propria T-cells collected from small intestinal tissues were isolated by identifying 7AAD-/CD45+TCRB+ cells using FACS. b) UMAP of 12,073 cells from healthy controls (n=2) and ulcerative colitis (n=1) and Crohn’s disease (n=1) patients. Cells were clustered into 18 clusters; the hCD4+CD8+, hTreg and hMAIT cluster is considered to be an ortholog of mouse CD4 cytotoxic T cells. c) Expression of CD4 and CD8A, d) Proportion of each cluster in controls and patients with ulcerative colitis (UC) and Crohn’s disease (CD).Human Cell AtlasThe Human Cell Atlas (HCA) is an international consortium Keio-RIKEN IMS HuMEDIn 2021, RIKEN IMS embarked on an exciting joint research
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