Control of gene expression in eukaryotes: STAT3 and hyper IgE syndrome

Transcription factors play an important role in controlling the expression of genes necessary for the maintenance of immune system function, and there are many examples of immune system diseases that originate with heritable mutations in transcription factor genes. For example, autosomal dominant hyper IgE syndrome (AD-HIES), a severe immunodeficiency disorder, is caused by a heterozygous mutation in the gene for the transcription factor signal transducer and activator of transcription 3 (STAT3). In healthy individuals, STAT3 resides in the cytoplasm, and is phosphorylated by receptors in the cell membrane upon binding with extracellular cytokines. The resulting activated protein, known as phospho-STAT3, binds a second phospho-STAT3 protein, and the resulting two-protein-complex (referred to as a “homodimer”) translocates to the nucleus and acts to initiate the transcription of many different genes, including the transcription factor retinoic acid-related orphan receptor gamma T (RORγT). RORγT controls important steps in the maturation process of T cells, and mutations affecting the STAT3 gene associated with AD-HIES manifest themselves in reduced populations of functional T cells.

Figure 1. Phospho-STAT3 homodimers translocate to the nucleus, where they bind DNA and initiate the transcription of genes, such as the gene coding for RORγT.

In order to better understand the relationship between transcription of STAT3 and RORγT in AD-HIES, researchers used a quantitative polymerase chain reaction assay to measure non-mutated STAT3 and RORγT messenger RNA (mRNA) levels in T cells derived from AD-HIES patients. The results, depicted in figure one, show a twofold decrease in non-mutated STAT3 mRNA levels in T cells of AD-HIES patients compared to control (healthy individuals), but a fourfold decrease in RORγT mRNA levels in the same cell populations.

Figure 2. STAT3 and RORγT mRNA levels in T cells of AD-HIES patients and in healthy individuals (control), measured in relative units.