Abstract 5511: Lineage-specific and shared cytokine-sensing genes respond distinctly to the master regulator STAT5

Abstract

Abstract JAK/STAT signaling pathways are critical for cell response to cytokines across multiple tissues, genetic variation in this pathway could associate with neoplastic diseases. STAT5, the most common used STAT family member, differently activates two distinct classes of genes. It activates cell-specific genes up to two orders of magnitude higher than shared genes expressed across different cell types. Socs2 (Suppressors of cytokine signaling 2), a widely expressed STAT5 target gene and a negative regulator of cytokine feedback loops, contains STAT5 response element within its promoter region. In our study, we demonstrated that STAT5 preferentially binds to promoter sequence of shared STAT5 targeted genes and to distal putative enhancers of lineage-specific genes. DNase-seq demonstrated that chromatin accessibility of STAT5-based enhancers was greatly dependent on cytokine exposure, while common STAT5 promoter targets were constitutively accessible. CRIPSR /Cas9 gene editing was used to delete the generic STAT5 binding sites in Socs2 locus in mice. Prolactin induction of Socs2 was abrogated both in liver and mammary gland, and resulted in elevated STAT5 activation and precocious mammary development in mutant mice. Taken together, we demonstrated that promoter-bound STAT5 modulates cytokine responses of universal STAT5 target genes, while enhancer-bound STAT5 is necessary for linage-specific target gene activation. This study provides new insight into the mechanism of used by a generic cytokine response element controlling lineage-specific transcription. Citation Format: xianke zeng, Michaela Willi, Ha Youn Shin, Chaochen Wang, Lothar Hennighausen. Lineage-specific and shared cytokine-sensing genes respond distinctly to the master regulator STAT5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5511. doi:10.1158/1538-7445.AM2017-5511