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Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):E3472-E3480. doi: 10.1073/pnas.1700946114. Epub 2017 Apr 10.

Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity.

Author information

1
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
2
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 cbdm@hms.harvard.edu.

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 (Foxp3 long intergenic noncoding RNA) is a negative regulator that tunes Foxp3 expression, resulting in a subset of Tregs with twofold- to fivefold-lower levels of FoxP3 protein. The impact of Flicr is particularly marked in conditions of IL-2 deficiency, and, conversely, IL-2 represses Flicr expression. Flicr neighbors Foxp3 in mouse and human genomes, is specifically expressed in mature Tregs, and acts only in cis It does not affect DNA methylation, but modifies chromatin accessibility in the conserved noncoding sequence 3 (CNS3)/Accessible region 5 (AR5) region of Foxp3 Like many lncRNAs, Flicr's molecular effects are subtle, but by curtailing Treg activity, Flicr markedly 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.

KEYWORDS:

Foxp3; autoimmunity; gene regulation; long noncoding RNA; regulatory T cells

PMID:
28396406
PMCID:
PMC5410798
DOI:
10.1073/pnas.1700946114
[Indexed for MEDLINE]
Free PMC Article

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