A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance

Dikiy, Stanislav; Li, Jun; Bai, Lu; Jiang, Menglin; Janke, Laura J.; Zong, Xinying; Hao, Xiaolei; Hoyos, Beatrice; Wang, Zhong-Min; Xu, Beisi; Fan, Yiping; Rudensky, Alexander Y.; Feng, Yang

doi:10.1016/j.immuni.2021.03.020

Cited by 55 publications

(64 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At d 4 when iT reg cells were fully induced, CNS0 deficiency did not affect H3K27ac levels at the Foxp3 promoter, which was comparable to CNS0-sufficient and CNS0-deficient nT reg cells. This result is consistent with the apparent roles of CNS0 and CNS3 in Foxp3 induction but not maintenance ( Dikiy et al, 2021 ). Foxp3 induction was significantly more impaired by C646 or JQ1 treatment in CNS0-deficient versus CNS0-sufficient cells despite their comparable effects on cell viability ( Figures 1K , 1L , S1J , and S1K ).…”

Section: Resultssupporting

confidence: 89%

See 1 more Smart Citation

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

et al. 2021

Cell Reports

Self Cite

View full text Add to dashboard Cite

SUMMARY Regulatory T (T reg ) cells play crucial roles in suppressing deleterious immune response. Here, we investigate how T reg cells are mechanistically induced in vitro (iT reg ) and stabilized via transcriptional regulation of T reg lineage-specifying factor Foxp3. We find that acetylation of histone tails at the Foxp3 promoter is required for inducing Foxp3 transcription. Upon induction, histone acetylation signals via bromodomain-containing proteins, particularly targets of inhibitor JQ1, and sustains Foxp3 transcription via a global or trans effect. Subsequently, Tet-mediated DNA demethylation of Foxp3 cis -regulatory elements, mainly enhancer CNS2, increases chromatin accessibility and protein binding, stabilizing Foxp3 transcription and obviating the need for the histone acetylation signal. These processes transform stochastic iT reg induction into a stable cell fate, with the former sensitive and the latter resistant to genetic and environmental perturbations. Thus, sequential histone acetylation and DNA demethylation in Foxp3 induction and maintenance reflect stepwise mechanical switches governing iT reg cell lineage specification.

show abstract

Section: Resultssupporting

confidence: 89%

“…Foxp3 enhancers CNS0, CNS1, and CNS3 haven been shown to facilitate Foxp3 induction ( Figure 1A ) ( Dikiy et al, 2021 ; Feng et al, 2015 ; Kawakami et al, 2021 ; Zheng et al, 2010 ; Zong et al, 2021 ). CNS3 acts through histone acetylation, at least partially, to enable efficient Foxp3 induction.…”

Section: Resultsmentioning

confidence: 99%

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

et al. 2021

Cell Reports

Self Cite

View full text Add to dashboard Cite

show abstract

“…To that end, the peripheral tolerance immune checkpoint molecules Cbl-b and Lyn were shown to cooperate with AIRE in modulating the development of autoimmune retinitis and exocrine pancreatitis in mice, respectively ( 17 , 18 ). In addition, when deficiency in the IL-2/STAT5 response regulatory element CNS0 was combined with AIRE deficiency in mice the result was exacerbation of autoimmune destruction in multiple organs, including in tissues (e.g., adipose tissue) that did not exhibit autoimmunity in isolated CNS0 or AIRE deficiencies ( 19 ).…”

Section: Genetics Of Apecedmentioning

confidence: 99%

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

2021

View full text Add to dashboard Cite

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.

show abstract

“…Disruption of Satb1-mediated SE activation not only leads to impaired Foxp3 induction but also diminishes DNA demethylation in Tregs-specific demethylation regions (TSDRs) [35]. This region is also bound by STAT5, and cooperatively with Il-2 enables Foxp3 induction in Tregs precursors, while its depletion together with Aire resulted in a worsened autoimmune disease [37]. Moreover, both naïve and activated Tregs comprise the Tregs-SEs, which correlate with Tregs-DRs (demethylated regions), affecting gene expression.…”

Section: Foxp3 Dna Methylationmentioning

confidence: 99%

“…Moreover, both naïve and activated Tregs comprise the Tregs-SEs, which correlate with Tregs-DRs (demethylated regions), affecting gene expression. What is more, autoimmune-disease-associated SNPs (single nucleotide polymorphisms), which affect Tregs function, are abundant in Treg-specific demethylated regions [37,38].…”

Section: Foxp3 Dna Methylationmentioning

confidence: 99%

Regulatory T Cells-Related Genes Are under DNA Methylation Influence

Piotrowska

Gliwiński

Trzonkowski

et al. 2021

IJMS

View full text Add to dashboard Cite

Regulatory T cells (Tregs) exert a highly suppressive function in the immune system. Disturbances in their function predispose an individual to autoimmune dysregulation, with a predominance of the pro-inflammatory environment. Besides Foxp3, which is a master regulator of these cells, other genes (e.g., Il2ra, Ctla4, Tnfrsf18, Ikzf2, and Ikzf4) are also involved in Tregs development and function. Multidimensional Tregs suppression is determined by factors that are believed to be crucial in the action of Tregs-related genes. Among them, epigenetic changes, such as DNA methylation, tend to be widely studied over the past few years. DNA methylation acts as a repressive mark, leading to diminished gene expression. Given the role of increased CpG methylation upon Tregs imprinting and functional stability, alterations in the methylation pattern can cause an imbalance in the immune response. Due to the fact that epigenetic changes can be reversible, so-called epigenetic modifiers are broadly used in order to improve Tregs performance. In this review, we place emphasis on the role of DNA methylation of the genes that are key regulators of Tregs function. We also discuss disease settings that have an impact on the methylation status of Tregs and systematize the usefulness of epigenetic drugs as factors able to influence Tregs functions.

show abstract

A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance

Cited by 55 publications

References 100 publications

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Regulatory T Cells-Related Genes Are under DNA Methylation Influence

Contact Info

Product

Resources

About