During this reporting period the Laboratory of Genetics and Physiology has continued and expanded a program aimed at exploring the interphase between cytokine-STAT5 signaling and epigenetic programming of cells. In particular we have addressed the question whether the ability of the transcription factor STAT5 to differentially activate genetic programs in distinct cell types and during specific developmental windows is influenced by the concentration of STAT5. In order to answer this question, we have generated mouse embryonic fibroblasts (MEFs) carrying three different genotypes, wild type MEFs, STAT5-null MEFs and MEFs containing 10-fold higher STAT5 concentrations than wild type MEFs. Using these MEFs containing different concentrations of STAT5 we performed ChIP-seq experiments to identify genome-wide the entire set of loci that interact with STAT5. Moreover, we performed corresponding gene expression analyses. LGP is currently working with computational biologists from KAIST and POSTECH (South Korea) to analyze these large data sets. In an extension of this program, LGP scientists have initiated mouse genetic experiments aimed at addressing the question whether the epigenetic landscape in mammary epithelium undergoes changes during pregnancy and whether this relates to the activation of developmental programs aimed at controlling cell proliferation and differentiation.

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Yoo, Kyung Hyun; Oh, Sumin; Kang, Keunsoo et al. (2015) Loss of EZH2 results in precocious mammary gland development and activation of STAT5-dependent genes. Nucleic Acids Res :
Bae, Woo Kyun; Kang, Keunsoo; Yu, Ji Hoon et al. (2015) The methyltransferases enhancer of zeste homolog (EZH) 1 and EZH2 control hepatocyte homeostasis and regeneration. FASEB J 29:1653-62
Bae, Woo Kyun; Yoo, Kyung Hyun; Lee, Ji Shin et al. (2015) The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers. Mol Carcinog 54:1172-80
Bae, Woo Kyun; Hennighausen, Lothar (2014) Canonical and non-canonical roles of the histone methyltransferase EZH2 in mammary development and cancer. Mol Cell Endocrinol 382:593-597
Zhu, Bing-Mei; Kang, Keunsoo; Yu, Ji Hoon et al. (2012) Genome-wide analyses reveal the extent of opportunistic STAT5 binding that does not yield transcriptional activation of neighboring genes. Nucleic Acids Res 40:4461-72
Yoo, Kyung Hyun; Hennighausen, Lothar (2012) EZH2 methyltransferase and H3K27 methylation in breast cancer. Int J Biol Sci 8:59-65