Machine learning-based prediction reveals kinase MAP4K4 regulates neutrophil differentiation through phosphorylating apoptosis-related proteins.

Journal: PLoS computational biology
PMID: 40096134

Abstract

Neutrophils, an essential innate immune cell type with a short lifespan, rely on continuous replenishment from bone marrow (BM) precursors. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the molecular regulators involved in the differentiation process remain poorly understood. Here we developed a random forest-based machine-learning pipeline, NeuRGI (Neutrophil Regulatory Gene Identifier), which utilized Positive-Unlabeled Learning (PU-learning) and neural network-based in silico gene knockout to identify neutrophil regulators. We interrogated features including gene expression dynamics, physiological characteristics, pathological relatedness, and gene conservation for the model training. Our identified pipeline leads to identifying Mitogen-Activated Protein Kinase-4 (MAP4K4) as a novel neutrophil differentiation regulator. The loss of MAP4K4 in hematopoietic stem cells and progenitors in mice induced neutropenia and impeded the differentiation of neutrophils in the bone marrow. By modulating the phosphorylation level of proteins involved in cell apoptosis, such as STAT5A, MAP4K4 delicately regulates cell apoptosis during the process of neutrophil differentiation. Our work presents a novel regulatory mechanism in neutrophil differentiation and provides a robust prediction model that can be applied to other cellular differentiation processes.

Authors

  • Guihua Wang
    Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
  • Dan Zhang
    School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
  • Zhifeng He
    School of Government and Law, Beijing Normal University, Zhuhai519087, China.
  • Bin Mao
    School of Medicine, Hunan Normal University, Changsha, China.
  • Xiao Hu
    Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, United States.
  • Li Chen
    Department of Endocrinology and Metabolism, Qilu Hospital, Shandong University, Jinan, China.
  • Qingxin Yang
    Institute of Urology, The Third Affiliated Hospital of Shenzhen University, Shenzhen, 518000, P. R. China.
  • Zhen Zhou
    Deepwise Healthcare, Beijing 100080, China.
  • Yating Zhang
    School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, PR China.
  • Kepan Linghu
    Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
  • Chao Tang
    School of Public Health, Dalian Medical University, Dalian, China.
  • Zijie Xu
    Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
  • Defu Liu
    Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
  • Junwei Song
    Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
  • Huiying Wang
    School of Nursing, Capital Medical University, Beijing, China.
  • Yishan Lin
    Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
  • Ruihan Li
    School of Computer Science, Hubei University of Technology, Wuhan 430068, China.
  • Jing-Wen Lin
    Biosafety Laboratory of West China Hospital, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • Lu Chen
    Ultrasonic Department, Zhongda Hospital Affiliated to Southeast University, Nanjing, 210009, China.

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