Downregulation of p53 by Insufficient CTCF in CD4+ T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease

Hua, Juan; Chen, Yan; Fu, Bin; Xu, Caigang; Xu, Xuejun; Yang, Shuanghui; Chen, Cong; Xu, Yajing

doi:10.3389/fimmu.2020.568637

Cited by 5 publications

(8 citation statements)

References 37 publications

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“…Our previous study confirmed that CTCF expression is reduced in CD4 + T cells from aGVHD patients compared with non-aGVHD cases [ 38 ]. To further explore the binding levels of CTCF in the AhR promoter region in CD4 + T cells from aGVHD patients, we assessed the binding levels of CTCF in the AhR promoter region in CD4 + T cells from aGVHD and non-aGVHD patients by ChIP-qPCR using anti-CTCF antibodies.…”

Section: Resultssupporting

confidence: 83%

“…Histone H3 Lys 9 (H3K9) and H3K14 are common acetylation sites for EP300 modifications and are considered hallmarks of activated gene transcription [ 36 , 37 ]. Our previous studies confirmed that CTCF expression is reduced in CD4 + T cells from aGVHD patients compared with non-aGVHD cases [ 38 ]. Therefore, we speculated that low expression of CTCF may reduce the interaction of TET2 with EP300 in the AhR promoter and induce AhR promoter DNA hypermethylation and histone H3K9/K14 hypoacetylation, leading to insufficient AhR expression.…”

Section: Introductionsupporting

confidence: 85%

“…TET2 and EP300, a methyl cytosine dioxygenase and a histone acetylase, respectively, were predicted to interact with CTCF. Our previous study confirmed that CTCF in CD4 + T cells could bind to EP300; so here we only assessed CTCF interaction with TET2 [ 38 ]. First, CTCF and TET2 expression plasmids were transfected into Jurkat cells, and co-immunoprecipitation was used to detect whether CTCF could form a complex with TET2.…”

Section: Resultsmentioning

confidence: 74%

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The absence of AhR in CD4+ T cells in patients with acute graft-versus-host disease may be related to insufficient CTCF expression

Zeng

Cheng

et al. 2022

Clin Epigenet

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Background Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Accumulating evidence suggests that imbalanced Treg/Th17 ratio accelerates the progression of aGVHD. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor activated through cognate ligand binding. Current evidence supports that AhR plays a critical regulatory role in the differentiation of Treg and Th17 cells. However, the relationship between AhR and aGVHD remains unclear. Results Our results showed that AhR expression was downregulated significantly in CD4+ T cells from patients with aGVHD compared with the non-aGVHD group. We also discovered that after activating AhR deficient CD4+ T cells, the expression levels of the activation markers-CD40L, CD134 and CD137 and cell proliferation activity were significantly higher than those of AhR-expressing CD4+ T cells. Restoring the expression of AhR in aGVHD CD4+ T cells resulted in significantly increased percentage of Tregs and associated gene transcripts, including Foxp3, IL-10 and CD39. In contrast, Th17 cell amounts and the transcription of related genes, including RORγt, IL-17A and IL-17F, were significantly reduced. We confirmed that CTCF recruited EP300 and TET2 to bind to the AhR promoter region and promoted AhR expression by mediating histone H3K9/K14 hyperacetylation and DNA demethylation in this region. The low expression of CTCF caused histone hypoacetylation and DNA hypermethylation of the AhR promoter, resulting in insufficient expression in aGVHD CD4+ T cells. Conclusions CTCF is an important inducer of AhR transcription. Insufficient expression of CTCF leads to excessive AhR downregulation, resulting in substantial CD4+ T cell activation and Th17/Treg ratio increase, thereby mediating the occurrence of aGVHD.

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Section: Resultssupporting

confidence: 83%

Section: Introductionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 74%

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The absence of AhR in CD4+ T cells in patients with acute graft-versus-host disease may be related to insufficient CTCF expression

Zeng

Cheng

et al. 2022

Clin Epigenet

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“…Expression of p53 was regulated by CTCF binding to its promoter region, which recruited the histone acetylase p300 to acetylate H3K9 and H3K14. Low CTCF expression caused an insufficient proliferative response to IL-2 and skewed T cells towards the Th17 phenotype ( 57 ).…”

Section: Cohesin-ctcf Dependent Genome Organization In Autoimmune Dis...mentioning

confidence: 99%

“…CTCF establishes and maintains open chromatin regions in nonlymphoid tissue Tregs ( 94 ), since the bulk of FOXP3 binding sites are found in repressed/poised chromatin ( 93 ). CTCF overexpression in CD4 + T cells increased expression of Foxp3 and decrease Rorγt ( 57 ). CTCF binding sites colocalized together with T reg -specific super-enhancers were required for expression of the T reg -signature genes including Foxp3 , Ctla4 , Il2RA and Ikzf2 , suggesting a reliance on cohesin/CTCF complexes for chromatin looping to facilitate proximity between super-enhancers and promoters ( 95 ).…”

Section: Immune Loci Regulation By the Cohesin Complexmentioning

confidence: 99%

Cohesin-Mediated Chromatin Interactions and Autoimmunity

et al. 2022

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Proper physiological functioning of any cell type requires ordered chromatin organization. In this context, cohesin complex performs important functions preventing premature separation of sister chromatids after DNA replication. In partnership with CCCTC-binding factor, it ensures insulator activity to organize enhancers and promoters within regulatory chromatin. Homozygous mutations and dysfunction of individual cohesin proteins are embryonically lethal in humans and mice, which limits in vivo research work to embryonic stem cells and progenitors. Conditional alleles of cohesin complex proteins have been generated to investigate their functional roles in greater detail at later developmental stages. Thus, genome regulation enabled by action of cohesin proteins is potentially crucial in lineage cell development, including immune homeostasis. In this review, we provide current knowledge on the role of cohesin complex in leukocyte maturation and adaptive immunity. Conditional knockout and shRNA-mediated inhibition of individual cohesin proteins in mice demonstrated their importance in haematopoiesis, adipogenesis and inflammation. Notably, these effects occur rather through changes in transcriptional gene regulation than through expected cell cycle defects. This positions cohesin at the crossroad of immune pathways including NF-kB, IL-6, and IFNγ signaling. Cohesin proteins emerged as vital regulators at early developmental stages of thymocytes and B cells and after antigen challenge. Human genome-wide association studies are remarkably concordant with these findings and present associations between cohesin and rheumatoid arthritis, multiple sclerosis and HLA-B27 related chronic inflammatory conditions. Furthermore, bioinformatic prediction based on protein-protein interactions reveal a tight connection between the cohesin complex and immune relevant processes supporting the notion that cohesin will unearth new clues in regulation of autoimmunity.

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IFN-γ induces acute graft-versus-host disease by promoting HMGB1-mediated nuclear-to-cytoplasm translocation and autophagic degradation of p53

Wang,

Cheng,

Chen

et al. 2024

Clinical Science

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Acute graft-versus-host disease (aGVHD) poses a significant impediment to achieving a more favourable therapeutic outcome in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our prior investigations disclosed a correlation between p53 downregulation in CD4+ T cells and the occurrence of aGVHD. Notably, the insufficiency of the CCCTC-binding factor (CTCF) emerged as a pivotal factor in repressing p53 expression. However, the existence of additional mechanisms contributing to the reduction in p53 expression remains unclear. Interferon (IFN)-γ, a pivotal proinflammatory cytokine, assumes a crucial role in regulating alloreactive T cell responses and plays a complex part in aGVHD development. IFN-γ has the capacity to induce autophagy, a vital catabolic process facilitating protein degradation, in various cell types. Presently, whether IFN-γ participates in the development of aGVHD by instigating the autophagic degradation of p53 in CD4+ T cells remains an unresolved question. In this study, we demonstrated that heightened levels of IFN-γ in the plasma during aGVHD promoted the activation, proliferation, and autophagic activity of CD4+ T cells. Furthermore, IFN-γ induced the nuclear-to-cytoplasm translocation and autophagy-dependent degradation of p53 in CD4+ T cells. The translocation and autophagic degradation of p53 were contingent upon HMGB1, which underwent upregulation and translocation from the nucleus to the cytoplasm following IFN-γ stimulation. In conclusion, our data unveil a novel mechanism underlying p53 deficiency in CD4+ T cells among aGVHD patients. This deficiency is induced by IFN-γ and relies on autophagy, establishing a link between IFN-γ, HMGB1-mediated translocation, and the autophagic degradation of p53.

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Downregulation of p53 by Insufficient CTCF in CD4+ T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease

Cited by 5 publications

References 37 publications

The absence of AhR in CD4+ T cells in patients with acute graft-versus-host disease may be related to insufficient CTCF expression

The absence of AhR in CD4+ T cells in patients with acute graft-versus-host disease may be related to insufficient CTCF expression

Cohesin-Mediated Chromatin Interactions and Autoimmunity

IFN-γ induces acute graft-versus-host disease by promoting HMGB1-mediated nuclear-to-cytoplasm translocation and autophagic degradation of p53

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