title: Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity.
abstract: A combination of transcription factors, enhancers, and epigenetic marks determines the expression of the key transcription factor FoxP3 in regulatory T cells (Tregs). Adding an additional layer of complexity, the long noncoding RNA (lncRNA)Flicr(Foxp3long intergenic noncoding RNA) is a negative regulator that tunesFoxp3expression, resulting in a subset of Tregs with twofold- to fivefold-lower levels of FoxP3 protein. The impact ofFlicris particularly marked in conditions of IL-2 deficiency, and, conversely, IL-2 repressesFlicrexpression.FlicrneighborsFoxp3in mouse and human genomes, is specifically expressed in mature Tregs, and acts only incisIt does not affect DNA methylation, but modifies chromatin accessibility in the conserved noncoding sequence 3 (CNS3)/Accessible region 5 (AR5) region ofFoxp3Like many lncRNAs,Flicr's molecular effects are subtle, but by curtailing Treg activity,Flicrmarkedly promotes autoimmune diabetes and, conversely, restrains antiviral responses. This mechanism of FoxP3 control may allow escape from dominant Treg control during infection or cancer, at the cost of heightened autoimmunity.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: David
authors.initials: D
authors.lastname: Zemmour
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Alvin
authors.initials: A
authors.lastname: Pratama
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Loughhead
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 cbdm@hms.harvard.edu.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 cbdm@hms.harvard.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D015551:Autoimmunity; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D015894:Genome, Human; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D062085:RNA, Long Noncoding / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D062085:RNA, Long Noncoding
keywords: Foxp3; autoimmunity; gene regulation; long noncoding RNA; regulatory T cells