Lineage-specific and non-specific cytokine-sensing genes respond differentially to the master regulator STAT5

Summary

STAT5, a member of the family of Signal Transducers and Activators of Transcription senses cytokines and controls the biology of cell lineages, including mammary, liver and T cells. Here we show that STAT5 activates lineage-specific and widely expressed genes through different mechanisms. STAT5 preferentially binds to promoter sequences of cytokine-responsive genes expressed across cell types and to putative enhancers of lineage-specific genes. While chromatin accessibility of STAT5-based enhancers was dependent on cytokine exposure, STAT5-responsive promoters of widely expressed target genes were generally constitutively accessible. While the contribution of STAT5 to enhancers is well established, its role on promoters is poorly understood. To address this we focused on Socs2, a widely expressed cytokine-sensing gene. Upon deletion of the STAT5 response elements from the Socs2 promoter, cytokine induction was abrogated, while basal activity remained intact. Our data suggest that promoter-bound STAT5 modulates cytokine responses and enhancer-bound STAT5 is mandatory for gene activation.

eTOC blurb

Zeng et al. find that the cytokine-sensing transcription factor STAT5 activates lineage-specific and widely expressed genes through different mechanisms. STAT5 controls lineage-specific genes through enhancers and widely expressed genes via promoters. While STAT5 is essential for the activation of cytokine-responsive enhancers, it merely modulates promoters upon cytokine stimulation.