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