Laboratory of Genetics and Physiology

About the Lab

The Laboratory of Genetics and Physiology (LGP) explores how cytokines activate cell-specific genetic programs, with an emphasis on the mammary gland. We use genome-wide technologies to identify complex regulatory elements that control mammary-specific gene transcription and investigate their structure and function using advanced genome and deaminase base-editing in mice.

Current Research

The emphasis of our research is on fundamental problems related to the activation of cell-specific genetic programs. Current research is aimed towards an understanding the genetic logic behind mammary-specific programs. LGP scientists have discovered that the JAK-STAT5 signaling pathway is essential for the establishment of the mammary gland and the activation of specific genetic programs during pregnancy. Using large-scale genomic approaches (ChIP-seq, Hi-C, RNA-seq), LGP scientists continue to explore the chromatin landscape of differentiating mammary cells as a means to identify putative key regulatory elements. Super-enhancers and other regulatory elements have been identified and their structures and functions are being investigated using tools of experimental genetics (2, 4-6). LGP scientists have not only used CRISPR/Cas9 genome editing technologies to interrogate gene regulation in vivo (2, 4-6), but they also investigated the fidelity of this fast-evolving technology. They have discovered that CRISPR/Cas9 can introduce extensive genomic damage at their target sites (3) but otherwise has no adverse impact on the mouse genome outside the target site (1). Most recently, LGP scientists have successfully used the more advanced genome editing technology of deaminase base editing to interrogate the mouse genome.

  1. Willi M, Smith HE, Wang C, Liu C, Hennighausen L (2018) Frequency of spurious mutations is not substantially increased by CRISPR-Cas9 genome editing. Nature Methods, in press.
  2. Willi M, Yoo KH, Reinisch F, Kuhns TM, Lee HK, Wang C, Hennighausen L (2017) Facultative CTCF sites moderate mammary super-enhancer activity and regulate juxtaposed gene in non-mammary cells. Nat Commun 8: 16069
  3. Shin HY, Wang C, Lee HK, Yoo KH, Zeng X, Kuhns T, Yang CM, Mohr T, Liu C, Hennighausen L (2017) CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome. Nat Commun 8: 15464
  4. Lee HK, Willi M, Wang C, Yang CM, Smith HE, Liu C, Hennighausen L (2017) Functional assessment of CTCF sites at cytokine-sensing mammary enhancers using CRISPR/Cas9 gene editing in mice. Nucleic Acids Res 45: 4606-4618
  5. Shin HY, Willi M, Yoo HK, Zeng X, Wang C, Metser G, Hennighausen L (2016) Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat Genet 48: 904-911
  6. Metser G, Shin HY, Wang C, Yoo KH, Oh S, Villarino AV, O'Shea JJ, Kang K, Hennighausen L (2016) An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic Acids Res 44: 1052-63

Current Collaborators:

  • Woo Kyun Bae (Gwangju, South Korea)
  • Simon Choi (Gwangju, South Korea)
  • Jason Kim (Gwangju, South Korea)
  • David Liu (Harvard, Broad)
  • Chengyu Liu (NHLBI, NIH)
  • Kyung Hyun Yoo (Seoul, South Korea)
  • Bing Mei Zhu (Chengdu, China)