Altered 3D genome reorganization mediates precocious myeloid differentiation of aged hematopoietic stem cells in inflammation

Xinyu Cui; Yu Dong; Qiang Zhan; Yixin Huang; Qianshu Zhu; Zihao Zhang; Guang Yang; Liping Wang; Shijun Shen; Jia Zhao; Zhiyi Lin; Jiatong Sun; Zhongqu Su; Yihan Xiao; Chuyu Zhang; Yuwei Liang; Lu Shen; Lichen Ji; Xuguang Zhang; Jiqing Yin; Hong Wang; Zhiyang Chen; Zhenyu Ju; Cizhong Jiang; Rongrong Le; Shaorong Gao

doi:10.1007/s11427-024-2754-9

Altered 3D genome reorganization mediates precocious myeloid differentiation of aged hematopoietic stem cells in inflammation

Sci China Life Sci. 2024 Dec 27. doi: 10.1007/s11427-024-2754-9. Online ahead of print.

Authors

Xinyu Cui^#^{1

2}, Yu Dong^#¹, Qiang Zhan^#³, Yixin Huang¹, Qianshu Zhu^{1

2}, Zihao Zhang^{1

2}, Guang Yang^{1

2}, Liping Wang^{1

2}, Shijun Shen^{1

2}, Jia Zhao^{1

2}, Zhiyi Lin¹, Jiatong Sun¹, Zhongqu Su⁴, Yihan Xiao¹, Chuyu Zhang¹, Yuwei Liang¹, Lu Shen¹, Lichen Ji⁵, Xuguang Zhang⁶, Jiqing Yin¹, Hong Wang¹, Zhiyang Chen⁷, Zhenyu Ju⁸, Cizhong Jiang^{9

10}, Rongrong Le¹¹, Shaorong Gao¹²

Affiliations

¹ 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, Shanghai, 200092, China.
² 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, Shanghai, 200092, China.
³ 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, Guangzhou, 510632, China.
⁴ Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian, 271018, China.
⁵ Department of Joint Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China.
⁶ Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
⁷ 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, Guangzhou, 510632, China. [email protected].
⁸ 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, Guangzhou, 510632, China. [email protected].
⁹ 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, Shanghai, 200092, China. [email protected].
¹⁰ 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, Shanghai, 200092, China. [email protected].
¹¹ 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, Shanghai, 200092, China. [email protected].
¹² 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, Shanghai, 200092, China. [email protected].

^# Contributed equally.

PMID: 39754007
DOI: 10.1007/s11427-024-2754-9

Abstract

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.

Keywords: 3D genome structure; CTCF; NF-κB; aging; hematopoietic stem cells; inflammation.