Geneformer-guided multiomics integration identifies Pbx1 as a network hub of hematopoietic stem cell aging
Hematopoietic stem cells (HSCs) constitute an organized hematopoietic system that undergoes age-related alterations, including increased platelet production and decreased erythropoiesis. The fundamental mechanisms driving these shifts remain incompletely understood. We used single-cell RNA sequencing data to show that old HSCs contain two distinct transcriptional programs: one shared with megakaryocytes and the other reflecting the most primitive HSC state. Developmental time-series profiling further suggests that the acquisition of these programs begins early in life, with the primitive module rising prenatally and megakaryocytic priming emerging after birth. Using a fine-tuned Geneformer (transformer-based deep learning model) to capture higher-order differences between young and old HSCs, coupled with transcriptomic and epigenetic profiling, as well as transcription factor screens, we identified Pbx1 as a key regulator of these age-related transcriptional and differentiation changes. Specifically, Pbx1 suppresses erythroid differentiation by repressing Gata1 expression. These findings provide insight into HSC aging and may inform approaches to modulate age-associated HSC dysfunction.
Authors
- Shuhei Koide (ORCID: https://orcid.org/0000-0001-8599-6115)
- Hiroshi Kobayashi (ORCID: https://orcid.org/0000-0002-0924-1252)
- Miho Haraguchi
- Atsushi Iwama (ORCID: https://orcid.org/0000-0001-9410-8992)
- Seishi Ogawa (ORCID: https://orcid.org/0000-0002-7778-5374)
- Keiyo Takubo (ORCID: https://orcid.org/0000-0002-1736-7592)
- Takayoshi Asakura
- Motohiko Oshima (ORCID: https://orcid.org/0000-0001-6991-815X)
- Shinpei Tamaki
- Toshio Miyata (ORCID: https://orcid.org/0000-0001-9153-5024)
- S. Watanuki (ORCID: https://orcid.org/0000-0002-9229-6712)
- Naoya Takayama (ORCID: https://orcid.org/0000-0001-6867-1677)
- Yusuke Shiozawa (ORCID: https://orcid.org/0000-0001-8673-677X)
- Takayuki Morikawa
Institutions
- Chiba University (JP)
- Tohoku University (JP)
- Kyoto University (JP)
- Innovation Center of NanoMedicine (JP)
- National Center for Global Health and Medicine (JP)
- Kanagawa Industrial Technology Center (JP)
- The University of Tokyo (JP)
- Nippon Medical School (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2026-08-21
- DOI
- https://doi.org/10.1126/sciadv.aeb1346
- Primary Topic
- Zebrafish Biomedical Research Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Takeda Science Foundation
- Cell Science Research Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- National Center for Global Health and Medicine
- Kanagawa Institute of Industrial Science and Technology
- Japan Health Research Promotion Bureau
- Kato Memorial Bioscience Foundation
- SENSHIN Medical Research Foundation
- Waksman Foundation of Japan
- Chemo-Sero-Therapeutic Research Institute