Altered 3D genome reorganization mediates precocious myeloid differentiation of aged hematopoietic stem cells in inflammation
作者机构：Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital Frontier Science Center for Stem Cells School of Life Sciences and Technology Tongji University Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education Orthopaedic Department of Tongji Hospital School of Life Sciences and Technology Tongji University Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine Department of Developmental & Regenerative Medicine College of Life Science and Technology Jinan University Shandong Key Laboratory of Animal Bioengineering and Disease Prevention College of Animal Science and Technology Shandong Agricultural University Department of Joint Surgery Shanghai East Hospital Tongji University School of Medicine Shanghai Institute of Nutrition and Health Chinese Academy of Sciences
出 版 物：《Science China Life Sciences》 (中国科学:生命科学(英文版))
年 卷 期：2025年
核心收录：
学科分类：0710[理学-生物学] 07[理学] 09[农学] 071007[理学-遗传学] 0901[农学-作物学] 090102[农学-作物遗传育种]
基 金：supported by the National Natural Science Foundation of China (32122030, 32470845, 32330030, 92168205, 92049304, 82030039, 32341004, 82230047, 32122030, 31721003, 32000562, 32170589, 31970758, 31972882, and 92049112) the Ministry of Science and Technology of China (2024YFA1107000, 2022YFC2702200, 2021YFC2700301, 2021YFA1100103, 2021YFA1100302, 2024YFA098701) the Science and Technology Innovation Action Plan of the Science and Technology Commission of Shanghai Municipality (21JC1405500) the innovation team project of universities in Guangdong province (2023KCXTD004) Shanghai Rising-Star Program (A type) of the Science, Technology Commission of Shanghai Municipality (21QA1409500) the Fundamental Research Funds for the Central Universities (22120240435) the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai the Guangdong Basic and Applied Basic Research Foundation (2022A1515011204)
摘 要：Inflammation is a driving force of hematopoietic stem cells(HSCs) aging, causing irreversible exhaustion of functional HSCs. However, the underlying mechanism of HSCs erosion by inflammatory insult remains poorly understood. Here, we find that transient LPS exposure primes aged HSCs to undergo accelerated differentiation at the expense of self-renewal, leading to depletion of HSCs. Meanwhile, the central regulator nuclear factor kappa B(NF-κB) mediating functional impairment by inflammation insult induces differential transcriptional response in aged HSCs compared with young HSCs, with precocious activation of myeloid lineage genes. Altered compartmentalization and chromatin loop formation are associated with aging-related differential transcriptional response in HSCs upon lipopolysaccharide(LPS)stimulation. Mechanistically, enhancer and promoter regions of myeloid lineage genes in aged HSCs are more accessible and display more rapid and prominent CTCF occupancy upon LPS stimulation. Our study provides comprehensive resources for the three-dimensional(3D)genome structure of HSCs and sheds light into the ordered genome organization and the associated transcriptome signature underlying HSCs aging.
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