Paper Reading
01
HydrogenSulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell
Differentiation and Maintain Immune Homeostasis
Ruili Yang, Cunye Qu et al.,Immunity
Regulatory T (Treg) cells are essential for maintenance of immune homeostasis. In this paper, the authors found that Treg Cells expressed cystathionine b-synthase(CBS) and cystathionine g-lyase (CSE), as well as Produced hydrogen sulfide(H2S). Further assays revealed that H2S was required for Foxp3+ Treg cell differentiation and function. H2S maintained expression of methylcytosine dioxygenases Tet1 and Tet2 via sulfhydration of nuclear transcription factor Ysubunit beta (NFYB) to facilitate NFYB"s binding to Tet1 and Tet2 promoters. Transforming growth factor-b (TGF-b)-activated Smad3 and interleukin-2(IL-2)-activated Stat5 recruited Tet proteins to Foxp3 locus. Tet1 and Tet2catalyzed conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine(5hmC) in Foxp3 to establish a Treg cell-specific hypomethylation pattern and stable Foxp3 expression. Consequently, loss of Tet1 and Tet2 led to Foxp3 hypermethylation, impaired Treg cell differentiation and function, and autoimmune disease. H2S Donor Treatment could Rescue Treg Cell Deficiency inCbs–/– Mice in a Tet-Dependent Manner. Therefore, the authors proposed that H2Spromoted Tet1 and Tet2 expression, which were recruited to Foxp3 by TGF-b andIL-2 signaling to maintain Foxp3 demethylation and Treg-cell-associated immunehomeostasis.
/10.1016/j.immuni..07.017
02
The Methylcytosine Dioxygenase Tet2 Promotes DNA Demethylation and Activation of Cytokine Gene Expression in T Cells
Kenji Ichiyama, Tingting Chen et al.,Immunity
Ten-eleven translocation (Tet) proteins catalyze 5-methylcytosine (5mC) conversion to 5-hydroxymethylcytosine (5hmC) to mediate DNA demethylation. In this study, the authors first generated genome-wide maps of 5mC and 5hmC modifications in Th cell subsets differentiated in vitro by use of high-throughput DIP-seq approach. They found that 5hmC was enriched in gene body and enhancer regions of lineage-specific genes in appropriate Th cells. However, a decrease of the overall amount of 5hmC was found when naive CD4+ T cells differentiated into effector cells. Tet2 was associated with 5hmC-containing regions. The recruitment of Tet2 and DNA demethylation was dependent upon key transcription factors such as T-bet,RORgt, and Stat3, indicating a critical role of these transcription factors in the active DNA demethylation and chromatin restructuring process during T celldifferentiation. Finally, via in vivo assays, they revealed that deletion of Tet2 in T cells decreased their cytokine expression, associated with reduced p300 recruitment. Therefore, Tet2 played an important role in regulating the expression of IL-10, IL-17, and IFN-g in vivo as well as in regulating T-cell-mediated autoimmune diseases. Collectively, the authors proposed that Tet-mediated active DNA demethylation was an essential epigenetic mechanism for regulation of Th cell function.
/10.1016/j.immuni..03.005
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