A highland-adaptation variant near MCUR1 reduces its transcription and attenuates erythrogenesis in Tibetans
To identify genomic regions subject to positive selection that might contain genes involved in high-altitude adaptation (HAA), we performed a genome-wide scan by whole-genome sequencing of Tibetan highlanders and Han lowlanders. We revealed a collection of candidate genes located in 30 genomic loci under positive selection. Among them, MCUR1 at 6p23 was a novel pronounced candidate. By single-cell RNA sequencing and comprehensive functional studies, we demonstrated that MCUR1 depletion leads to impairment of erythropoiesis under hypoxia and normoxia. Mechanistically, MCUR1 knockdown reduced mitochondrial Ca<sup>2+</sup> uptake and then concomitantly increased cytosolic Ca<sup>2+</sup> levels, which thereby reduced erythropoiesis via the CAMKK2-AMPK-mTOR axis. Further, we revealed rs61644582 at 6p23 as an expression quantitative trait locus for MCUR1 and a functional variant that confers an allele-specific transcriptional regulation of MCUR1. Overall, MCUR1-mediated mitochondrial Ca<sup>2+</sup> homeostasis is highlighted as a novel regulator of erythropoiesis, deepening our understanding of the genetic mechanism of HAA.
Authors
- Yongquan Cui
- Huiping Ma
- Yiming Lu (ORCID: https://orcid.org/0000-0001-8005-2705)
- Bing Su (ORCID: https://orcid.org/0000-0003-0871-7666)
- Huifang Liu (ORCID: https://orcid.org/0000-0002-2008-1325)
- Xiaojun Wei (ORCID: https://orcid.org/0000-0002-6229-6228)
- Cheng Quan (ORCID: https://orcid.org/0000-0003-1859-9683)
- Shizheng Wu
- Yuqing Jiang (ORCID: https://orcid.org/0000-0003-3638-7828)
- Jie Ping (ORCID: https://orcid.org/0000-0001-9907-5819)
- Ouzhuluobu
- Haoxiang Zhang (ORCID: https://orcid.org/0000-0003-2531-5028)
- Hao Guo (ORCID: https://orcid.org/0000-0002-0688-5431)
- Wangshan Zheng (ORCID: https://orcid.org/0000-0002-6174-4746)
- Cuiling Wang (ORCID: https://orcid.org/0000-0002-1399-1048)
- Ping Yu Fan (ORCID: https://orcid.org/0000-0003-3618-6639)
- Longli Kang (ORCID: https://orcid.org/0000-0001-6881-3241)
- Linpeng Yang
- Wanjun Jin (ORCID: https://orcid.org/0009-0000-4777-5581)
- Shunqi Chen
- Gangqiao Zhou (ORCID: https://orcid.org/0000-0002-4895-5063)
- Jie Liu (ORCID: https://orcid.org/0000-0002-1415-3847)
- Yuanfeng Li (ORCID: https://orcid.org/0000-0001-8227-7019)
- Yaoxi He (ORCID: https://orcid.org/0000-0003-3324-3239)
- Yang Zhang (ORCID: https://orcid.org/0000-0002-3998-177X)
- Xinyi Liu (ORCID: https://orcid.org/0000-0003-0241-5499)
- Zheng Zhang (ORCID: https://orcid.org/0009-0003-2498-9693)
- Xianwei Wang (ORCID: https://orcid.org/0000-0002-1490-8736)
- Peihao Yin (ORCID: https://orcid.org/0009-0001-1496-1107)
- Yuan Wei (ORCID: https://orcid.org/0000-0003-3387-7549)
- Hui Juan Lu (ORCID: https://orcid.org/0000-0001-8347-0830)
- Hongxing Zhang (ORCID: https://orcid.org/0009-0008-5178-3021)
- Mengyu Liu (ORCID: https://orcid.org/0000-0003-4155-2189)
- Lu Hao (ORCID: https://orcid.org/0000-0002-9622-031X)
- Ri‐Li Ge
- Guanjun Liu (ORCID: https://orcid.org/0000-0001-8454-2904)
- Ying Cui (ORCID: https://orcid.org/0000-0001-9201-0465)
- Yujia Zhai (ORCID: https://orcid.org/0000-0003-4697-5797)
- Fuchu He (ORCID: https://orcid.org/0000-0002-1094-4019)
- Tana Wuren
- Ying Hao (ORCID: https://orcid.org/0000-0001-7599-5813)
- Lingle Chang
- Yuting Wang (ORCID: https://orcid.org/0009-0007-7345-0562)
- Qilin Huang
- Xuebin Qi
Institutions
- Kunming University of Science and Technology (CN)
- Qinghai University (CN)
- Guangxi Medical University (CN)
- Xizang Minzu University (CN)
- Beijing University of Chinese Medicine (CN)
- Guizhou University (CN)
- Capital Medical University (CN)
- Kunming Institute of Zoology (CN)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Beijing Chao-Yang Hospital, Capital Medical University (CN)
- People's Liberation Army 401 Hospital (CN)
- Institute of Primate Research (KE)
- Lanzhou Army General Hospital (CN)
- Qinghai Tibetan Hospital (CN)
- Henan Provincial People's Hospital (CN)
- Peking University Third Hospital (CN)
- Henan Cancer Hospital (CN)
- Beijing Proteome Research Center (CN)
- Qinghai Provincial Peoples Hospital (CN)
- Tumor Hospital of Guangxi Medical University (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.xgen.2025.100782
- Citations
- 4
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 3.75