Cell-specific significance of a common cytokine responsive enhancer

Authors

• X Zeng
• HY Shin
• C Wang
• L Hennighausen

Abstract

This study addresses the fundamental, yet unanswered question how a common transcription factor asserts context-dependent cell-specific and general transcriptional control. The family of transcription factor STATs executes the biology of virtually every cytokine across multiple cell types and tissues. Activated STATs bind to defined target sequences and control transcription of cell-specific and common target genes, such as Socs2. SOCS2 (Suppressor of cytokine signaling 2) is implicated in the negative regulation of the JAK/STAT pathways. This feedback loop is thought to precisely control cellular STAT activity. Although the Socs2 gene can be activated by many cytokines through STATs, the molecular basis of its cell-specific regulation remains unclear. To further understand the cell-specific regulation of the Socs2 locus by STATs, and in particular STAT5, we compared its binding patterns in mammary tissue, T cells and liver. While STAT5 binding in the promoter region was observed in mammary tissue and T cells, lineage-specific binding was obtained to sites as far upstream as 46 kbp. These sites coincide with H3K27ac enhancer marks. The biological significance of these sites was studied in mice from which they had been deleted using CRIPSR/Cas9 gene editing. The impact of these mutations on gene expression, epigenome status and biological function was examined across tissues. Notably, loss of the promoter proximal common STAT5 binding site resulted mammary-specific phenotypes and precocious activation of mammary alveolar development during pregnancy. This provides evidence that a feedback loop between cytokine-induced STAT5 and its target Socs2 ensures strict temporal control of cellular differentiation during pregnancy.

Scientific Focus Area: Genetics and Genomics

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