Identification of STAT5A and STAT5B Target Genes in Human T Cells

Abstract

<div><p>Signal transducer and activator of transcription (STAT) comprises a family of universal transcription factors that help cells sense and respond to environmental signals. STAT5 refers to two highly related proteins, STAT5A and STAT5B, with critical function: their complete deficiency is lethal in mice; in humans, STAT5B deficiency alone leads to endocrine and immunological problems, while STAT5A deficiency has not been reported. STAT5A and STAT5B show peptide sequence similarities greater than 90%, but subtle structural differences suggest possible non-redundant roles in gene regulation. However, these roles remain unclear in humans. We applied chromatin immunoprecipitation followed by DNA sequencing using human CD4⁺ T cells to detect candidate genes regulated by STAT5A and/or STAT5B, and quantitative-PCR in <i>STAT5A</i> or <i>STAT5B</i> knock-down (KD) human CD4⁺ T cells to validate the findings. Our data show STAT5A and STAT5B play redundant roles in cell proliferation and apoptosis via <i>SGK1</i> interaction. Interestingly, we found a novel, unique role for STAT5A in binding to genes involved in neural development and function (<i>NDRG1</i>, <i>DNAJC6</i>, and <i>SSH2</i>), while STAT5B appears to play a distinct role in T cell development and function via <i>DOCK8</i>, <i>SNX9</i>, <i>FOXP3</i> and <i>IL2RA</i> binding. Our results also suggest that one or more co-activators for STAT5A and/or STAT5B may play important roles in establishing different binding abilities and gene regulation behaviors. The new identification of these genes regulated by STAT5A and/or STAT5B has major implications for understanding the pathophysiology of cancer progression, neural disorders, and immune abnormalities.</p></div