TGF-beta signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity

doi:10.1084/jem.20190550

	TGF-beta signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity
	Sun, Xiang 1; Cui, Yu 1; Feng, Haiyun2 ; Liu, Haifeng 1; Liu, Xiaolong1,2
	2019-12
发表期刊	JOURNAL OF EXPERIMENTAL MEDICINE
ISSN	0022-1007
EISSN	1540-9538
卷号	216 期号:12 页码:2819-2837
发表状态	已发表
DOI	10.1084/jem.20190550
摘要	Regulatory T(T reg) cells are required for the maintenance of immune homeostasis. Both TGF-beta signaling and epigenetic modifications are important for Foxp3 induction, but how TGF-beta signaling participates in the epigenetic regulation of Foxp3 remains largely unknown. Here we showed that T cell-specific ablation of Uhrf1 resulted in T reg-biased differentiation in TCR-stimulated naive T cells in the absence of TGF-beta signaling, and these Foxp3(+) T cells had a suppressive function. Adoptive transfer of Uhrf1(-1-) naive T cells could significantly suppress colitis due to increased iT reg cell generation. Mechanistically, Uhrf1 was induced upon TCR stimulation and participated in the maintenance of DNA methylation patterns of T reg cell-specific genes during cell division, while it was phosphorylated upon TGF-beta stimulation and sequestered outside the nucleus, and ultimately underwent proteasome-dependent degradation. Collectively, our study reveals a novel epigenetic mechanism of TGF-beta-mediated iT reg cell differentiation by modulating Uhrf1 activity and suggests that Uhrf1 may be a potential therapeutic target in inflammatory diseases for generating stable iT reg cells.
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收录类别	SCI ; SCIE
语种	英语
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences[XDB19000000]
WOS研究方向	Immunology ; Research & Experimental Medicine
WOS类目	Immunology ; Medicine, Research & Experimental
WOS记录号	WOS:000523636900010
出版者	ROCKEFELLER UNIV PRESS
WOS关键词	DNA METHYLATION ; TRANSCRIPTION FACTOR ; CIS-ELEMENT ; EXPRESSION ; DNMT1 ; PHOSPHORYLATION ; INDUCTION ; STABILITY ; UBIQUITIN ; GENE
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/119341
专题	生命科学与技术学院_硕士生生命科学与技术学院_特聘教授组_刘小龙组
通讯作者	Liu, Xiaolong
作者单位	1.Chinese Acad Sci, Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol,State Key Lab C, Shanghai, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Sun, Xiang,Cui, Yu,Feng, Haiyun,et al. TGF-beta signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity[J]. JOURNAL OF EXPERIMENTAL MEDICINE,2019,216(12):2819-2837.
APA	Sun, Xiang,Cui, Yu,Feng, Haiyun,Liu, Haifeng,&Liu, Xiaolong.(2019).TGF-beta signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity.JOURNAL OF EXPERIMENTAL MEDICINE,216(12),2819-2837.
MLA	Sun, Xiang,et al."TGF-beta signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity".JOURNAL OF EXPERIMENTAL MEDICINE 216.12(2019):2819-2837.