Reciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4

Nature Communications
Lucia Campos CarrascosaMagdalena Huber

Abstract

The T helper 9 (Th9) cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Here we show that, within this network, two interferon regulatory factors (IRF), IRF1 and IRF4, display opposing effects on Th9 differentiation. IRF4 dose-dependently promotes, whereas IRF1 inhibits, IL-9 production. Likewise, IRF1 inhibits IL-9 production by human Th9 cells. IRF1 counteracts IRF4-driven Il9 promoter activity, and IRF1 and IRF4 have opposing function on activating histone modifications, thus modulating RNA polymerase II recruitment. IRF1 occupancy correlates with decreased IRF4 abundance, suggesting an IRF1-IRF4-binding competition at the Il9 locus. Furthermore, IRF1 shapes Th9 cells with an interferon/Th1 gene signature. Consistently, IRF1 restricts the IL-9-dependent pathogenicity of Th9 cells in a mouse model of allergic asthma. Thus our study reveals that the molecular ratio between IRF4 and IRF1 balances Th9 fate, thus providing new possibilities for manipulation of Th9 differentiation.

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Citations

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Datasets Mentioned

BETA
GEX60815
GSE96818
GSE96699

Methods Mentioned

BETA
histone acetylation
immunoprecipitation
ChIP-Seq
acetylation
ChIP
transgenic
lavage
RNA-Seq
flow cytometry
flow

Software Mentioned

NGSplot
MACS2
Rsubread
STAR aligner
topGO Bioconductor
ENSEMBL
DESeq2
GraphPad Prism
DREME
Biostrings

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