IFN-α suppresses GATA3 transcription from a distal exon and promotes H3K27 trimethylation of the CNS-1 enhancer in human Th2 cells.
IFN-α suppresses GATA3 transcription from a distal exon and promotes H3K27 trimethylation of the CNS-1 enhancer in human Th2 cells.
复制标题
DOI：
10.4049/jimmunol.1301908
复制
发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Farrar JD
中科院分区：
文献类型：
--
作者：
Huber JP;Gonzales-van Horn SR;Roybal KT;Gill MA;Farrar JD
CD4+ T 辅助细胞 2 型 (Th2) 发育受锌指转录因子 GATA3 调节。一旦受到 IL-4 等急性启动信号的诱导，GATA3 就会使 Th2 细胞因子位点快速激活，并建立一个正反馈环，维持 GATA3 表达升高。 I 型干扰素 (IFN-α/β) 通过在 Th2 发育过程中和完全定向的 Th2 细胞中阻断 GATA3 的表达来抑制 Th2 细胞。在这项研究中，我们发现了 IFN-α/β 信号传导抑制人类 Th2 细胞中 GATA3 基因的独特机制。 IFN-α/β 抑制从另一个远端上游外显子 (1A) 转录的 GATA3 mRNA 的表达。这种抑制不是通过 DNA 甲基化介导的，而是通过位于外显子 1A 上游的保守非编码序列 (CNS-1) 的组蛋白修饰介导的。通过 DNase I 超敏性评估，IFN-α/β 治疗导致 CNS-1 形成闭合构象，同时该 CNS 区域 H3K27me3 标记积累增强，这与该假定增强子处总核小体密度的增加相关。因此，即使在 IL-4 存在的情况下，CNS-1 与 GATA3 DNA 结合活性的可及性也会因 IFN-α/β 信号传导而降低。因此，IFN-α/β 会破坏 GATA3 自激活环，并促进 GATA3 基因内 Th2 特异性调控区域的表观遗传沉默。
CD4+ T helper type 2 (Th2) development is regulated by the zinc finger transcription factor GATA3. Once induced by acute priming signals, such as IL-4, GATA3 poises the Th2 cytokine locus for rapid activation and establishes a positive feedback loop that maintains elevated GATA3 expression. Type I interferon (IFN-α/β) inhibits Th2 cells by blocking the expression of GATA3 during Th2 development and in fully committed Th2 cells. In this study, we have uncovered a unique mechanism by which IFN-α/β signaling represses the GATA3 gene in human Th2 cells. IFN-α/β suppressed expression of GATA3 mRNA that was transcribed from an alternative distal upstream exon (1A). This suppression was not mediated through DNA methylation, but rather by histone modifications localized to a conserved non-coding sequence (CNS-1) upstream of exon 1A. IFN-α/β treatment lead to a closed conformation of CNS-1 as assessed by DNase I hypersensitivity along with enhanced accumulation of H3K27me3 mark at this CNS region, which correlated with increased density of total nucleosomes at this putative enhancer. Consequently, accessibility of CNS-1 to GATA3 DNA binding activity was reduced in response to IFN-α/β signaling, even in the presence of IL-4. Thus, IFN-α/β disrupts the GATA3 autoactivation loop and promotes epigenetic silencing of a Th2-specific regulatory region within the GATA3 gene.
登录
查看更多内容
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
DOI：
10.4049/jimmunol.181.12.8204
发表时间：
2008-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Davis AM;Ramos HJ;Davis LS;Farrar JD
通讯作者：
Farrar JD
影响因子：
4.4
作者：
Ben-Sasson, SZ;Gerstel, R;Paul, WE
通讯作者：
Paul, WE
DOI：
10.1073/pnas.1206629109
发表时间：
2012-11-27
影响因子：
11.1
作者：
Schneiderman, Jonathan I.;Orsi, Guillermo A.;Ahmad, Kami
通讯作者：
Ahmad, Kami
影响因子：
32.4
作者：
Bird, JJ;Brown, DR;Reiner, SL
通讯作者：
Reiner, SL