Fetal hepatocytes protect the HSPC genome via fetuin-A
The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development<sup>1-3</sup>. Although numerous cell-intrinsic mechanisms have been revealed<sup>4-7</sup>, little is known about genome-protective effects and influences of developmental tissue microenvironments on tissue-forming cells. Here we show that fetal liver hepatocytes provide protection to haematopoietic stem and progenitor cell (HSPC) genomes. Lineage tracing and depletion in mice demonstrated that delayed hepatocyte development in early fetal livers increased the chromosomal instability of newly colonizing HSPCs. In addition, HSPCs developed tolerance to genotoxins in hepatocyte-conditioned medium, suggesting that hepatocytes protect the HSPC genome in a paracrine manner. Proteomic analyses demonstrated the enrichment of fetuin-A in hepatocyte-conditioned medium but not in early fetal livers. Fetuin-A activates a Toll-like receptor pathway to prevent pathogenic R-loop accumulation in HSPCs undergoing DNA replication and gene transcription in the fetal liver. Numerous haematopoietic regulatory genes frequently involved in leukaemogenic mutations are associated with R-loop-enriched regions. In Fetua-knockout mice, HSPCs showed increased genome instability and susceptibility to malignancy induction. Moreover, low concentrations of fetuin-A correlated with the oncogenesis of childhood leukaemia. Therefore, we uncover a mechanism operating in developmental tissues that offers tissue-forming cell genome protection and is implicated in developmental-related diseases.
Authors
- Fan Bai (ORCID: https://orcid.org/0000-0001-6119-8936)
- Lei Chen (ORCID: https://orcid.org/0000-0002-6581-0544)
- Ruoyan Li (ORCID: https://orcid.org/0000-0001-5337-9729)
- Hua Zhu (ORCID: https://orcid.org/0000-0001-7136-7326)
- Renyan Wu
- Liang Chen (ORCID: https://orcid.org/0000-0002-6748-9416)
- Fang Ke (ORCID: https://orcid.org/0000-0002-5970-2512)
- Tariq Enver (ORCID: https://orcid.org/0000-0002-0866-6443)
- Juan Yu (ORCID: https://orcid.org/0000-0002-3474-3131)
- Huaifang Li (ORCID: https://orcid.org/0000-0002-9496-7145)
- Dengli Hong (ORCID: https://orcid.org/0000-0001-5251-0297)
- Zhi‐Qi Xiong (ORCID: https://orcid.org/0000-0001-7727-8412)
- Hongyu Xie (ORCID: https://orcid.org/0000-0001-6386-8083)
- Yiding Wang (ORCID: https://orcid.org/0000-0002-6596-2337)
- Guohong Li (ORCID: https://orcid.org/0000-0003-2137-0783)
- Li Shuiping
- Lei Chu (ORCID: https://orcid.org/0000-0002-6626-8312)
- Ye Hu (ORCID: https://orcid.org/0000-0001-7255-5409)
- Xiaolin Guo
- Guoqiang Chen (ORCID: https://orcid.org/0000-0003-4936-2363)
- Y. G. Liu (ORCID: https://orcid.org/0009-0003-4850-4929)
Institutions
- Tongji University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Ruijin Hospital (CN)
- Shanghai Innovative Research Center of Traditional Chinese Medicine (CN)
- Wuhan University (CN)
- Shanghai Children's Medical Center (CN)
- Institute of Biophysics (CN)
- CRUK Lung Cancer Centre of Excellence (GB)
- Tongji Hospital (CN)
- University College London (GB)
- Hainan Medical University (CN)
Publication Details
- Journal
- Nature
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s41586-024-08307-x
- Citations
- 11
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 2.57
Funders
- Medical Research Council