한빛사논문
- 조회441
Yongsik Cho #,1,2,3, Hyeonkyeong Kim #,1,2,3, Geunho Yook #,1,2, Sangmin Yong 1,2, Soy Kim 1,2, Narae Lee 1,2, Yi-Jun Kim 4, Jin-Hee Kim 5, Tae Woo Kim 6, Moon Jong Chang 6, Kyoung Min Lee 6, Chong Bum Chang 7, Seung-Baik Kang 6, Jin-Hong Kim 1,2,8
1Center for RNA Research, Institute for Basic Science, 08826, Seoul, South Korea.
2Department of Biological Sciences, College of Natural Sciences, Seoul National University, 08826, Seoul, South Korea.
3Liflex Science, 28160, Cheongju, South Korea.
4Department of Occupational and Environmental Medicine, College of Medicine, Ewha Womans University, 07985, Seoul, South Korea.
5Department of Biomedical Laboratory Science, College of Health Science, Cheongju University, 28503, Cheongju, South Korea.
6Department of Orthopedic Surgery, Seoul National University College of Medicine, Boramae Hospital, 07061, Seoul, South Korea.
7Department of Orthopedic Surgery, Seoul National University Bundang Hospital, 13620, Seongnam, South Korea.
8Interdisciplinary Program in Bioinformatics, Seoul National University, 08826, Seoul, South Korea.
#Contributed equally.
Authorship contribution: Y.C., H.K., G.Y. contributed equally to this work.
CORRESPONDING AUTHOR : Jin-Hong Kim PhD
Abstract
Objective: Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have suggested its potential function in DNA repair. However, the physiological significance of this non-canonical function remains unexplored. Here, we investigated IRF1's role in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation.
Methods: OA progression was examined in wild-type and Irf1-/- mice using histological assessments and micro-computed tomography (μCT) analysis of whole-joint OA manifestations, and behavioral assessments of joint pain. An integrated analysis of ATAC-seq and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ-H2AX foci and senescence-associated β-galactosidase (SA-β-Gal) activity.
Results: Our genome-wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes, without noticeable footprint patterns in those of interferon-responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was downregulated in the cartilage of human and mouse OA. While IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post-traumatic OA in mice.
Conclusion: IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.
논문정보
- Research article
- 2024년 01월 (BRIC 등록일 2024-01-29)
- 국내 연구진
- 생명과학 > 노화/암생물학
관련 보도자료
- Bio통신원
- 2024. 01. 31
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