PIM1通過抑制重編程誘導的鐵下垂和細胞周期阻滯促進肝臟轉化

2022年9月6日，中國醫學科學院北京協和醫學院生物醫學工程研究所，上海工業大學生命科學與技術學院，分子生物物理教育部重點實驗室，湖北省生物信息學與分子成像重點實驗室，人工智能生物學中心，華中生命科學與技術學院人工智能研究所，武漢科技大學，復旦大學眼耳鼻喉醫院耳鼻喉科，醫學神經生物學與生物醫學研究所國家重點實驗室，國家衛生健康委聽力醫學重點實驗室，南京大學人工智能生物醫學研究所，香港轉化干細胞生物學中心有限公司（Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.

School of Life Scienceand Technology, ShanghaiTech University, Shanghai 201210, China.

MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, Institute of Artificial Intelligence, College of Life Science and Technology, Huazhong

University of Science and Technology, Wuhan 430074 Hubei, China.

ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and Institutes of Biomedical Sciences, Fudan University, Shanghai 200031, China.

NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China.

Nanjing University Institute of Artificial Intelligence Biomedicine, Nanjing, Jiangsu 210031, China.

Present address: Centre for Translational Stem Cell Biology Limited, Hong Kong 999077, China.） Yu Xue & Pengyu Huang研究團隊，在《nature communications 》發表了論文，標題為：“PIM1 promotes hepatic conversion by suppressing reprogramming-induced ferroptosis and cell cycle arrest”“PIM1通過抑制重編程誘導的鐵下垂和細胞周期阻滯促進肝臟轉化”

Abstract

Protein kinase-mediated phosphorylation plays a critical role in many biological processes.   However, the identification of key regulatory kinases is still a great challenge.   Here, we develop a trans-omics-based method, central kinase inference, to predict potentially key kinases by integrating quantitative transcriptomic and phosphoproteomic data.   Using known kinases associated with anti-cancer drug resistance, the accuracy of our method denoted by the area under the curve is 5.2% to 29.5% higher than Kinase-Substrate Enrichment Analysis.   We further use this method to analyze trans-omic data in hepatocyte maturation and hepatic reprogramming of human dermal fibroblasts, uncovering 5 kinases as regulators in the two processes.   Further experiments reveal that a serine/threonine kinase, PIM1, promotes hepatic conversion and protects human dermal fibroblasts from reprogramming-induced ferroptosis and cell cycle arrest.   This study not only reveals new regulatory kinases, but also provides a helpful method that might be extended to predict central kinases involved in other biological processes.

摘要

蛋白激酶介導的磷酸化在許多生物過程中起著關鍵作用。然而，關鍵調控激酶的鑒定仍然是一個巨大的挑戰。在這里，我們開發了一種基于反式組學的方法，中央激酶推斷，通過整合定量轉錄組學和磷酸化蛋白質組學數據來預測潛在的關鍵激酶。使用已知的與抗癌藥物耐藥相關的激酶，我們的方法的曲線下面積表示的準確度比激酶底物富集分析高出5.2%至29.5%。我們進一步利用這種方法分析了肝細胞成熟和人類真皮成纖維細胞肝臟重編程的反組學數據，發現了5種激酶在這兩個過程中起調節作用。進一步的實驗表明，絲氨酸/蘇氨酸激酶PIM1促進肝臟轉化，并保護人類真皮成纖維細胞免受重編程誘導的鐵凋亡和細胞周期阻滯。這項研究不僅揭示了新的調控激酶，而且提供了一種有用的方法，可以擴展到預測參與其他生物過程的中樞激酶。

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