Melissa A. Henriksen, PhD
Clare Boothe Luce Assistant Professor
Education & Training
B.S., The College of the Holy Cross, Worcester, MA
1990, Chemistry
Ph.D., The University of Pennsylvania, Philadelphia, PA
1996, Biological Chemistry
The Rockefeller University, New York, NY
Laboratory of Molecular Cell Biology, 1996-2005
Postdoctoral Fellow, Research Associate
Research Assistant Professor
Head of Laboratory: Professor James E. Darnell, Jr.
Introduction to the Henriksen Lab
The STAT Signaling Pathway, Molecular Mechanisms of Gene Expression, Chromatin Biology and Epigenetics
Our lab's primary research objective is to define the epigenetic changes that regulate STAT induced transcription. In response to a variety of extracellular ligands, the STATs (Signal Transducer and Activator of Transcription) are rapidly recruited from their latent state in the cytoplasm to cell surface receptors where they are activated by phosphorylation at a single tyrosine residue. Members of the JAK family of tyrosine kinases sometimes carry out the phosphorylation but many receptor and non-receptor tyrosine kinases activate STATs as well. Once phosphorylated the STATs dimerize and translocate to the nucleus where they bind specific DNA elements to drive the transcription of target genes, affecting growth, differentiation, homeostasis and the immune response. Within 1-2 hours, the active STATs are dephosphorylated and return to the cytoplasm. Thus, STAT signaling in driving gene expression is rapid and transient.
Not surprisingly, given their widespread involvement in normal cell processes, dysregulation of STAT function contributes to human disease, particularly to cancers. Constitutively active Stat3 is present in breast cancers, head and neck cancers, prostate cancers, multiple myeloma, leukemias and lymphomas. Stat5 that is persistently activated is found in some leukemias and lymphomas as well. Persistent activation of Stat1 in development can lead to dwarfism and the chronic conditions of asthma and Crohn's disease are also attributed to misregulated STAT activity. Even in the fruit fly, a gain of function mutation in a JAK homolog that activates Drosophila STAT (STAT92E) results in a phenotype that resembles leukemia.
The STATs ability to quickly trigger gene expression is intimately tied to chromatin architecture. Chromatin, DNA and the histones around which DNA is wrapped, is the template for all eukaryotic genetic information. It is the target of a number of post-translational modifications, (acetylation, phosphorylation, methylation and ubiquitylation), which impact its structure and thus, the regulation of gene activity. While we have learned much about how STATs coordinate with other transcription factors to induce transcription, and how this pathway is negatively regulated, little is understood about how changes to the chromatin template contribute to the regulation of gene expression. Thus, we have set out to survey the histone modifications that occur when Stat1 signaling is triggered by interferon treatment of mammalian cells. Using chromatin immunoprecipitation (ChIP) and quantitative PCR, we assay for changes in methylation, acetylation and phosphorylation at particular residues in the histone tails, as well as for histone variant swapping, across loci that are known targets Stat1. We then study how these moieties are regulated during STAT signaling and investigate which complexes are responsible for making the marks, which ones are recruited to the marks and which ones remove the marks. Our chief aim is to more fully understand how gene expression in response STAT signaling is controlled so that new therapeutic approaches might be developed to treat the diseases caused by improper STAT function.
