The Long Non-coding RNA Flatr Anticipates Foxp3 Expression in Regulatory T Cells.

Aleksandra Brajic,Oliver Burton,Simon Bornschein,Dean Franckaert,Adrian Liston,Susan Schlenner,Sofie Demeyer,Jan Cools,James Dooley,Anna L Calvanese

doi:10.3389/fimmu.2018.01989

Abstract

Mammalian genomes encode a plethora of long non-coding RNA (lncRNA). These transcripts are thought to regulate gene expression, influencing biological processes from development to pathology. Results from the few lncRNA that have been studied in the context of the immune system have highlighted potentially critical functions as network regulators. Here we explored the nature of the lncRNA transcriptome in regulatory T cells (Tregs), a subset of CD4+ T cells required to establish and maintain immunological self-tolerance. The identified Treg lncRNA transcriptome showed distinct differences from that of non-regulatory CD4+ T cells, with evidence of direct shaping of the lncRNA transcriptome by Foxp3, the master transcription factor driving the distinct mRNA profile of Tregs. Treg lncRNA changes were disproportionally reversed in the absence of Foxp3, with an enrichment for colocalisation with Foxp3 DNA binding sites, indicating a direct coordination of transcription by Foxp3 independent of the mRNA coordination function. We further identified a novel lncRNA Flatr, as a member of the core Treg lncRNA transcriptome. Flatr expression anticipates Foxp3 expression during in vitro Treg conversion, and Flatr-deficient mice show a mild delay in in vitro and peripheral Treg induction. These results implicate Flatr as part of the upstream cascade leading to Treg conversion, and may provide clues as to the nature of this process.

Highlights

Sequencing of the human genome showed that there are only ∼20,000 protein-coding genes, which is comparable to other less complex organisms such as nematodes or the fruit fly
Comparative expression analysis found that 13.8% of long non-coding RNA (lncRNA) expressed by Tregs were differentially expressed when compared to expression in naïve CD4+ T cells, with 190 lncRNA upregulated in Tregs and 55 lncRNA downregulated in Tregs (Figure 1A)
Forkhead box P3 (Foxp3) binds with multiple protein partners [33, 34], which can in turn bind to ∼700 gene targets [21] and either enhance or suppress the expression of the lncRNA Flatr Anticipates Foxp3 Expression resulting mRNA, depending on the composition of the complex [34]

Summary

Introduction

Sequencing of the human genome showed that there are only ∼20,000 protein-coding genes, which is comparable to other less complex organisms such as nematodes or the fruit fly. Recent studies indicate that the ∼35,000 mammalian lncRNA play a significant role in orchestrating and fine-tuning transcriptional programs both in health and disease [1,2,3]. These lncRNAs can be located within the nucleus or the cytoplasm of a cell and may or may not be polyadenylated. LncRNAs can be categorized into groups according to their localization (intronic, intergenic) and transcriptional direction (sense, antisense, bidirectional) [1]

Methods

Results

Conclusion