Research Projects
Human Cell Atlas
Research Overview
Multimodal benchmarking dataset of the human renal cortex (Ref. 4)
A) UMAP visualization of 119,744 nuclei and cells profiled using multiple single-cell modalities, including multiome snRNA-seq, multiome snATAC-seq, 3’scRNA-seq, and 5’scRNA-seq. B) Alluvial plots showing the distribution of cells across different experimental protocols, with colors indicating L1/L2 cell-type annotations. C) Heritability enrichment of hypertension and estimated glomerular filtration rate (eGFR) within cell type-specific cis-regulatory elements (CREs) defined by chromatin accessibility. D) Comparison of heritability enrichment using cell type-specific CREs defined by different strategies. Incorporating transcriptional information into CRE selection (Set 2) or prioritizing CREs based on transcriptional activity (Set 3) resulted in significantly greater heritability enrichment (p < 0.05) than using chromatin accessibility alone (Set 1), demonstrating the added value of integrating transcriptional and accessibility signals for identifying disease-relevant regulatory elements.
The Human Cell Atlas (HCA) is an international consortium dedicated to creating a comprehensive molecular reference map of all human cells, providing a foundation for understanding human health and disease. At RIKEN IMS, under the leadership of Dr. Piero Carninci, Dr. Jay Shin, and Dr. Chung-Chau Hon, we contribute to the HCA through three major activities: coordinating HCA initiatives across Asia (e.g., HCA Asia meetings), developing innovative single-cell experimental and computational technologies, and generating large-scale cellular atlases from Asian populations, including the Asian Immune Diversity Atlas (AIDA). A major contribution from our team is the development of a transcribed cis-regulatory element (tCRE) atlas based on single-cell 5’ RNA sequencing. This resource comprises more than one million cells from 32 human tissues and catalogs over 526,000 tCREs, substantially expanding the known landscape of human cis-regulatory elements. The atlas revealed that broadly expressed promoters are linked to highly cell type-specific distal regulatory elements, providing new insights into the organization of gene regulatory networks. Beyond serving as a reference resource, the atlas has enabled a number of downstream biological discoveries, including the identification of estrogen-responsive regulatory programs in cortical bone metabolism (Ref. 1) and the characterization of molecular mechanisms underlying adverse effects associated with progestin-primed ovarian stimulation (Ref. 2). Building upon this resource, we developed a tCRE module-based framework for evaluating complex trait heritability at single-cell resolution, enabling the identification of cell type-specific gene regulatory mechanisms underlying human diseases. This framework was subsequently applied to the AIDA project, which profiles more than 1.5 million immune cells from 619 healthy donors representing seven population groups across five Asian countries (Ref. 3). In collaboration with members of the HCA Standards and Technology Working Group, Dr. Piero Carninci and Dr. Chung-Chau Hon further benchmarked the tCRE-based analytical framework against other single-cell modalities using human kidney tissues (Figures A and B; Ref. 4). These analyses demonstrated that integrating transcriptional and chromatin accessibility signals improves both the sensitivity and biological interpretability of trait heritability analyses, enabling more precise identification of disease-relevant cell populations and regulatory programs (Figures C and D).
Contributed by Dr. Piero Carninci and Dr. Chung-Chau Hon
Reference:
1. Ikedo A, Aoki R, Sakai H, Saeki N, Yanagihara Y, Moody J, Kojima M, Kouno T, Ando Y, Hino K, Kinoshita T, Carninci P, Shin JW, Hon CC, Uezumi A, Kamei Y, Imai Y. Estrogen signaling in PDGFRα+ cells positively regulates cortical bone metabolism via IGFBP5 in female mice. JBMR Plus. 2025 Nov 7;10(1):ziaf178.
2. Handa M, Takiuchi T, Kawaguchi S, Hon CC, Moody J, Okazaki Y, Ozaki K, Horie M, Ohara Y, Doshida M, Takeuchi T, Matsubayashi H, Saji F, Miyake T, Ishikawa T, Ando Y, Komukai S, Kitamura T, Shin JW, Kimura T. Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis. Reprod Biomed Online. 2025 Aug;51(2):104833.
3. Kock KH, Tan LM, Han KY, Ando Y, Jevapatarakul D, Chatterjee A, Lin QXX, Buyamin EV, Sonthalia R, Rajagopalan D, Tomofuji Y, Sankaran S, Park MS, Abe M, Chantaraamporn J, Furukawa S, Ghosh S, Inoue G, Kojima M, Kouno T, Lim J, Myouzen K, Nguantad S, Oh JM, Rayan NA, Sarkar S, Suzuki A, Thungsatianpun N, Venkatesh PN, Moody J, Nakano M, Chen Z, Tian C, Zhang Y, Tong Y, Tan CTY, Tizazu AM, Loh M, Hwang YY, Ho RC, Larbi A, Ng TP, Won HH, Wright FA, Villani AC, Park JE, Choi M, Liu B, Maitra A, Pithukpakorn M, Suktitipat B, Ishigaki K, Okada Y, Yamamoto K, Carninci P, Chambers JC, Hon CC, Matangkasombut P, Charoensawan V, Majumder PP, Shin JW, Park WY, Prabhakar S. Asian diversity in human immune cells. Cell. 2025 Mar 19:S0092-8674(25)00202-8.
4. Acera-Mateos M, Adiconis X, Li JK, Marchese D, Caratù G, Hon CC, Tiwari P, Kojima M, Vieth B, Murphy MA, Simmons SK, Lefevre T, Claes I, O'Connor CL, Menon R, Otto EA, Ando Y, Vandereyken K, Kretzler M, Bitzer M, Fraenkel E, Voet T, Enard W, Carninci P, Heyn H, Levin JZ, Mereu E. Systematic evaluation of single-cell multimodal data integration enhances cell type resolution and discovery of clinically relevant states in complex tissues. Genome Biol. 2026 Mar 13;27(1):64.