TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis

Suga, Kyôichi; Suto, Akira; Tanaka, Shigeru; Sugawara, Yutaka; Kageyama, Takahiro; Ishikawa, Junichi; Sanayama, Yoshie; Ikeda, Kei; Furuta, Shunsuke; Kagami, Shin-ichiro; Iwata, Arifumi; Hirose, Koichi; Suzuki, Kotaro; Ohara, Osamu; Nakajima, Hiroshi

doi:10.1172/jci.insight.164778

Cited by 5 publications

(1 citation statement)

References 64 publications

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“…One requirement for increased TET activity may be in the regulation of immune responses. In regulatory T (Treg) cells, vitamin C promotes DNA demethylation of a Foxp3 enhancer, promoting Treg differentiation and immunosuppressive function akin to the role of low-dose MTX in rheumatoid arthritis patients (Yue et al, 2021;Suga et al, 2023). Vitamin C also drives oxidized methylcytosine formation and DNA demethylation within the three enhancers of the Prdm1 locus that are silenced in naive B cells but require activation for plasma cell differentiation (Qi et al, 2020).…”

Section: Hydroxymethylation Formation and Dna Methylation Removal Via...mentioning

confidence: 99%

Micronutrient regulation of the DNA methylome

Leesang,

Lyon,

Pinzone

et al. 2024

Front. Epigenet. Epigenom.

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The formation, inheritance, and removal of DNA methylation in the genome of mammalian cells is directly regulated by two families of enzymes–DNA methyltransferases (DNMTs) and Ten-Eleven Translocation proteins (TETs). DNMTs generate and maintain the inheritance of 5-methylcytosine (5mC), which is the substrate targeted by the TET enzymes for conversion to 5-hydroxymethylcytosine (5hmC) and its downstream oxidized derivatives. The activity of DNMT and TET is dependent on the availability of micronutrients and metabolite co-factors, including essential vitamins, amino acids, and trace metals, highlighting how DNA methylation levels can be directly enhanced, suppressed, or remodeled via metabolic and nutritional perturbations. Dynamic changes in DNA methylation are required during embryonic development, lineage specification, and maintenance of somatic cell function that can be fine-tuned based on the influence of essential micronutrients. As we age, DNA methylation and hydroxymethylation levels drift in patterning, leading to epigenetic dysregulation and genomic instability that underlies the formation and progression of multiple diseases including cancer. Understanding how DNA methylation can be regulated by micronutrients will have important implications for the maintenance of normal tissue function upon aging, and in the prevention and treatment of diseases for improved health and lifespan.

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Section: Hydroxymethylation Formation and Dna Methylation Removal Via...mentioning

confidence: 99%

Micronutrient regulation of the DNA methylome

Leesang,

Lyon,

Pinzone

et al. 2024

Front. Epigenet. Epigenom.

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Remodeling of T-cell mitochondrial metabolism to treat autoimmune diseases

Lin,

Ren,

Xiong

et al. 2024

Autoimmunity Reviews

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Stage-specific GATA3 induction promotes ILC2 development after lineage commitment

Furuya,

Toda,

Iwata

et al. 2024

Nat Commun

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Group 2 innate lymphoid cells (ILC2s) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 is a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains unclear. Herein, we identify ILC2-specific GATA3-related tandem super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 deficiency in the bone marrow, lung, liver, and small intestine with minimal impact on other ILC lineages or Th2 cells. Single-cell RNA-sequencing and subsequent flow cytometry analysis show that GATA3 induction mechanism, which is required for entering the ILC2 stage, is lost in IL-17RB+PD-1− late ILC2-committed precursor stage in G3SE-deficient mice. Cnot6l, part of the CCR4-NOT deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings implicate a stage-specific regulatory mechanism for GATA3 expression during ILC2 development.

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TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis

Cited by 5 publications

References 64 publications

Micronutrient regulation of the DNA methylome

Micronutrient regulation of the DNA methylome

Remodeling of T-cell mitochondrial metabolism to treat autoimmune diseases

Stage-specific GATA3 induction promotes ILC2 development after lineage commitment

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