title: Function of a Foxp3 cis-element in protecting regulatory T cell identity.
abstract: The homeostasis of multicellular organisms requires terminally differentiated cells to preserve their lineage specificity. However, it is unclear whether mechanisms exist to actively protect cell identity in response to environmental cues that confer functional plasticity. Regulatory T (Treg) cells, specified by the transcription factor Foxp3, are indispensable for immune system homeostasis. Here, we report that conserved noncoding sequence 2 (CNS2), a CpG-rich Foxp3 intronic cis-element specifically demethylated in mature Tregs, helps maintain immune homeostasis and limit autoimmune disease development by protecting Treg identity in response to signals that shape mature Treg functions and drive their initial differentiation. In activated Tregs, CNS2 helps protect Foxp3 expression from destabilizing cytokine conditions by sensing TCR/NFAT activation, which facilitates the interaction between CNS2 and Foxp3 promoter. Thus, epigenetically marked cis-elements can protect cell identity by sensing key environmental cues central to both cell identity formation and functional plasticity without interfering with initial cell differentiation.
authors.affiliation: Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Li
authors.affiliation: Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: LeBlanc
authors.affiliation: The Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.affiliation: Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: yzheng@salk.edu.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D017124:Conserved Sequence; D018899:CpG Islands; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015870:Gene Expression; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D012045:Regulatory Sequences, Nucleic Acid; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse