2. Academic Validation
  3. Dynamic O-GlcNAcylation governs long-range chromatin interactions in V(D)J recombination during early B-cell development

Dynamic O-GlcNAcylation governs long-range chromatin interactions in V(D)J recombination during early B-cell development

  • Cell Mol Immunol. 2025 Jan;22(1):68-82. doi: 10.1038/s41423-024-01236-9.
Bong Chan Jeon # 1 2,  Yu-Ji Kim # 1,  Ae Kyung Park # 3,  Mi-Ran Song 1,  Ki Myeong Na 1 2,  Juwon Lee 3,  Dasom An 4,  Yeseul Park 4,  Heeyoun Hwang 4,  Tae-Don Kim 2 5,  Junghyun Lim 6,  Sung-Kyun Park 7 8
Affiliations

Affiliations

  • 1 Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
  • 2 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea.
  • 3 Department of Pharmacy, School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju, Republic of Korea.
  • 4 Digital OMICs Research Center, Korea Basic Science Institute, Cheongju, Republic of Korea.
  • 5 Center for Cell and Gene Therapy, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
  • 6 Department of Pharmacy, School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju, Republic of Korea. jl1206@jbnu.ac.kr.
  • 7 Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea. skpark@kribb.re.kr.
  • 8 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea. skpark@kribb.re.kr.
  • # Contributed equally.
PMID: 39627609 DOI: 10.1038/s41423-024-01236-9
Abstract

V(D)J recombination secures the production of functional immunoglobulin (Ig) genes and antibody diversity during the early stages of B-cell development through long-distance interactions mediated by cis-regulatory elements and trans-acting factors. O-GlcNAcylation is a dynamic and reversible posttranslational modification of nuclear and cytoplasmic proteins that regulates various protein functions, including DNA-binding affinity and protein-protein interactions. However, the effects of O-GlcNAcylation on proteins involved in V(D)J recombination remain largely unknown. To elucidate this relationship, we downregulated O-GlcNAcylation in a mouse model by administering an O-GlcNAc inhibitor or restricting the consumption of a regular diet. Interestingly, the inhibition of O-GlcNAcylation in mice severely impaired Ig heavy-chain (IgH) gene rearrangement. We identified several factors crucial for V(D)J recombination, including YY1, CTCF, SMC1, and SMC3, as direct targets of O-GlcNAc modification. Importantly, O-GlcNAcylation regulates the physical interaction between SMC1 and SMC3 and the DNA-binding patterns of YY1 at the IgH gene locus. Moreover, O-GlcNAc inhibition downregulated DDX5 protein expression, affecting the functional association of CTCF with its DNA-binding sites at the IgH locus. Our results showed that locus contraction and long-range interactions throughout the IgH locus are disrupted in a manner dependent on the cellular O-GlcNAc level. In this study, we established that V(D)J recombination relies on the O-GlcNAc status of stage-specific proteins during early B-cell development and identified O-GlcNAc-dependent mechanisms as new regulatory components for the development of a diverse antibody repertoire.

Keywords

Cohesin complex; DDX5; O-GlcNAcylation; V(D)J recombination; YY1 and CTCF DNA binding.

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