Cytokines, STATs and chromatin

Our team explores genetic circuitry that integrates the JAK-STAT signaling pathway with other transcription factors and chromatin modeling in the process of mammary development during pregnancy.  Using traditional and cell-specific gene knock-out mice, researchers in LGP have discovered that cytokine-STAT5 signaling is essential for the development and function of several distinct cell types, including mammary alveolar progenitors and the luminal compartment. 

Current research focuses on the question how generic transcription factors, such as STAT5 and NF1, control specific developmental programs in mammary epithelium and other cell types.  Emphasis is on understanding the role of chromatin modifications and modeling in the specific cell-specific activation and repression of genetic programs. 

            To address these questions we perform genome-wide analyses to explore and understand the interaction of STAT5 and other transcription factors to genetic networks involved in mammary development and how these interactions are influenced by a changing chromatin landscape.  We also use mouse genetics to interrogate the relevance of genes and gene networks that control chromatin modeling.  Another focus in our laboratory is on micro RNA genes that are under the control of cytokines and STAT5.  To interrogate their function we are deleting pertinent micro RNA genes in specific cell types of the mouse, including mammary and hematopoietic stem cells.

Histone modifications and chromatin modeling in STAT5-dependent specification and differentiation of mammary cell lineages

Prolactin and its downstream transcription factor STAT5 are cornerstones of mammary alveolar development during pregnancy.  They control the establishment of the alveolar progenitor pool and subsequent proliferation and differentiation of alveolar luminal cells, which culminates in the production of milk.  STAT5 therefore controls distinct temporally- and context-dependent genetic programs.  During puberty STAT5 controls the establishment of the progenitor pool, during the early phase of pregnancy it activates cell proliferation and, as pregnancy progresses, its role in promoting cell differentiation becomes prominent.  Although these programs exhibit significant temporal overlap it can be hypothesized that STAT5 in cooperation with other transcription factors activates distinct genetic programs to achieve its different goals in the formation of the mammary gland. 

Ongoing research focuses on three venues.

• Identification of STAT5-activated genetic programs throughout pregnancy
• Role of chromatin modifications in alveolar development
• Synergy of Nuclear factor 1 (NF1) and STAT5 in alveolar differentiatio
  

To explore these questions we use a set of experimental approaches.  These include

• mouse genetics to delete relevant genes involved in chromatin modeling as well as NF1 genes
• ChIP-seq analyses to identify context-dependent binding of STAT5 and NF1 to chromatin
• ChIP-seq analyses to explore the changing chromatin landscape as alveolar cells progress through their developmental journey