Lineage-Specific and Non-specific Cytokine-Sensing Genes Respond Differentially to the Master Regulator STAT5

Abstract

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.

Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1/TLX1-Positive T Cell Acute Lymphoblastic Leukemia

“…Our finding that STAT5 and TLX1 regulate the expression of their target genes mainly through binding of more accessible enhancer regions indicates that leukemia development in this model is mainly driven by cell-identity-specific genes ( Hnisz et al., 2013 , Zeng et al., 2016 ). TLX1- and STAT5-occupied regions were bound by typical enhancer marks BRD4 and p300, both of which are necessary for transcriptional elongation, and were also marked by H3K27 acetylation.…”

CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome

“…To obtain in-depth knowledge on the extent of molecular consequences at target sites, we analysed deletions introduced at 17 loci in the mouse genome. By directly injecting the Cas9 machinery into mouse zygotes, we targeted five enhancers bound by the cytokine-sensing TF STAT5 in three genomic loci, Stat5a (A) 20 , Socs2 (B) 26 and Wap (C) 19 ( Fig. 1 ).…”

“…Additional detailed analyses were performed in 54 lines established from specific founders. Specifically, we deleted sequences in enhancers bound by the transcription factor (TF) STAT5 (refs 19 , 25 , 26 ) and sequences recognized by CTCF ( DOI: 10.1093/nar/gkx185 ), a protein known to aid in the establishment of functional chromatin loops. We investigated the molecular consequences on targeting sites with single sgRNAs and identified prevalent asymmetric deletions, preferred sites at which deletion occurs and large deletions.…”

Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer

“…Enhancer selection by STAT5 is cytokine-dependent, and the stability and function of STAT5 at enhancers and promoters is well characterized [ 101 ]. However, the ways in which STAT5 can affect surrounding chromatin upon binding to its target sites is less understood.…”