RHS6 coordinately regulates the Th2 cytokine genes by recruiting GATA3, SATB1, and IRF4

Asthma is a Th2 cell-driven inflammatory disease and a major public health concern. The cis-acting element Rad50 hypersensitive site 6 (RHS6) in the Th2 locus control region is essential for regulation of the Th2 cytokine genes; however, its role in allergic airway inflammation and underlying molecular mechanisms of the regulation by RHS6 are poorly understood.

We sought to understand the role of RHS6 in the development of allergic airway inflammation and its molecular mechanism for Th2 cytokine expression.

We used an ovalbumin-induced allergic inflammation model with RHS6-deficient mice to examine the role of RHS6 in this process. To examine molecular mechanism of RHS6 for Th2 cytokine expression, we used DNA affinity chromatography and mass spectrometry, quantitative RT-PCR, ELISA, intracellular cytokine staining, chromatin immunoprecipitation, and co-immunoprecipitation.

Deletion of RHS6 caused a dramatic resistance to allergic airway inflammation. RHS6 recruited transcription factors GATA3, SATB1, and IRF4, which play important roles in expression of all three Th2 cytokine genes. RHS6 deficiency caused inhibition of transcription factor-induced Th2 cytokine gene expression.

RHS6 is a critical regulatory element for allergic airway inflammation and for coordinate regulation of Th2 cytokine genes by recruiting GATA3, SATB1, and IRF4.