Lothar Hennighausen, Ph.D.

Senior Investigator

Laboratory of Genetics and Physiology

NIDDK

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Building 8, Room 101
8 Center Drive
Bethesda, MD 20814

301-328-6183

lotharh@helix.nih.gov

Research Topics

Research Goal

Our ultimate goal is to unlock the genetic and epigenetic switches used to control normal biology and pathobiology.​

Current Research

The Laboratory of Genetics and Physiology (LGP) explores genetic and epigenetic circuitry that controls the biology of the mammary gland and liver. Our goal is to understand how hormonal switches utilize transcription factors and chromatin modifying enzymes to activate cell specific genetic programs. Such programs are employed in normal development and disease. To achieve this goal we employ contemporary genetics, large-scale genomics and computational biology.

Researchers in LGP have discovered that prolactin controls mammary development during pregnancy and the establishment of lactation through the transcription factor STAT5. Although we understand the framework by which transcription factors control genetic programs, puzzling observations force scientists to rethink “established” concepts. For example, STAT5 binds to thousands of genes but only activates small subsets in specific cells, raising questions about the biological significance of “non-productive” transcription factor binding.

Current research explores the role of specific histone modifications in the establishment of cell-specific genetic programs. Towards this goal we have inactivated histone methyltransferases (EZH1, EZH2, MLL3, MLL4) and demethylates (UTX and JMJD3) in mammary tissue and liver. These studies not only shed light onto epigenetic mechanisms used to establish mammary stem cells but also in the protection of liver from disease.

Applying our Research

Our team has identified genetic switches that are used not only to control the normal physiology of cells, but also to induce disease when inappropriately regulated. For example, the transcription factor STAT5 is essential for the function of the immune system and the maintenance of blood and liver function. Aberrant activation or loss of this “benevolent” regulator can cause hematopietic disorders and liver disease.

Need for Further Study

Although transcription factors, such as STAT5, are present in every cell, their function is very cell specific. In mammary cells STAT5 activates genetic programs needed to make milk, and programs in erythroid cells ensure the production of blood. It remains an enigma why one protein can execute different programs in specialized cells.

Biography

  • Ph.D., University of Cologne, 1982
  • M.S., University of Cologne, 1979
  • B.S., Philipp University of Marburg, 1977

Selected Publications

  1. Yamaji D, Kang K, Robinson GW, Hennighausen L. Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration. Nucleic Acids Res. 2013;41(3):1622-36.

  2. Shin HY, Wang C, Lee HK, Yoo KH, Zeng X, Kuhns T, Yang CM, Mohr T, Liu C, Hennighausen L. CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome. Nat Commun. 2017;8:15464.

  3. Metser G, Shin HY, Wang C, Yoo KH, Oh S, Villarino AV, O'Shea JJ, Kang K, Hennighausen L. An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic Acids Res. 2016;44(3):1052-63.

  4. Shin HY, Willi M, HyunYoo K, Zeng X, Wang C, Metser G, Hennighausen L. Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat Genet. 2016;48(8):904-911.

  5. Yoo KH, Oh S, Kang K, Hensel T, Robinson GW, Hennighausen L. Loss of EZH2 results in precocious mammary gland development and activation of STAT5-dependent genes. Nucleic Acids Res. 2015;43(18):8774-89.

Related Scientific Focus Areas

This page was last updated on July 22nd, 2016