Melissa A. Henriksen

Education

  • BS, The College of the Holy Cross, Worcester, MA
  • PhD, The University of Pennsylvania, Philadelphia, PA
  • Postdoc, The Rockefeller University, New York, NY

Primary Appointment

  • Assistant Professor, Biology

Contact

Research Interest(s)

Chromatin Biology and Epigenetics, Cancer Stem Cells; Molecular Mechanisms of Gene Expression, STAT Signaling Pathway.

Research Description

STAT Signaling and Chromatin Biology



We study 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. 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.  

Epigenetics and a cancer stem cell



We investigate the epigenetics underlying the cellular heterogeneity in Neuroblastoma.The hallmark of cancer is uncontrolled cell proliferation and a tumor is typically considered a mass of exponentially growing cells. The ‘cancer stem cell’ hypothesis recently called the latter idea into question by demonstrating that a subpopulation of cells is endowed with properties that other cells in the tumor do not possess. They can both self-renew and differentiate. Treatments that fail to destroy these ‘cancer stem cells’ will only shrink a tumor and cancer will recur. Cancer stem cells have been reported in leukemia, colon, brain, breast, ovarian and just recently, pancreatic cancers and their discovery has revolutionized cancer biology research.

Our collaborators in the Ross laboratory at Fordham University identified the stem cell that contributes to the neural cancer, Neuroblastoma (NB), the most commonly diagnosed tumor in infants and young children. NB is a cancer of the neural crest, a transient embryonic structure that gives rise to a heterogeneous population of cells including neuroblasts, non-neuronal cells and melanocytes and this cellular heterogeneity is typical of tumors in neuroblastoma. The Ross lab has defined three phenotypically distinct cell types, intermediate (I)-type, neuroblastic (N) and substrate adherent (S) cells that contribute to NB tumors. S cells resemble non-neuronal, stromal cells and remarkably are not at all tumorigenic. N cells retain some tumor potential and are sympathoadrenal neuroblasts. The I-type cells are highly tumorigenic and capable of differentiation to both N and S cells identifying them as the cancer stem cells in NB.

Microarray studies have identified a cadre of differentially expressed genes in each cell type, providing insight into how transcription profiles correlate with already established phenotypes. What have not been investigated, however, are the epigenetic mechanisms I-type, N and S cells employ to establish their cellular identities and maintain them from one generation to the next. Our experimental strategy takes a whole genome approach by using ChIP-chip assays to investigate the status of chromatin at the promoter of every gene in the human genome in I-type stem cells and the differentiated N and S cells.

Chromatin carries not just the genetic information encoded by the DNA sequence but also epigenetic information borne by the histone proteins in their chemically modified tails. The cell understands this epigenetic information and the structure and function of chromatin are modulated appropriately. When it is misunderstood, cancer is often the result. Research focused on the role of epigenetic changes in cancer stem cells intends to provide for advances in cancer prevention, diagnosis and treatment.

Selected Publications

  • Auriemma L, Shah S, Linden L, Henriksen M. Knockdown of menin affects pre-mRNA processing and promoter fidelity at the interferon-gamma inducible IRF1 gene. Epigenetics & chromatin. 2012;5(1): 2. PMID: 22240255 | PMCID: PMC3271985
  • Chipumuro E, Henriksen M. The ubiquitin hydrolase USP22 contributes to 3'-end processing of JAK-STAT-inducible genes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2011;26(2): 842-54. PMID: 22067483
  • Shah S, Henriksen M. A novel disrupter of telomere silencing 1-like (DOT1L) interaction is required for signal transducer and activator of transcription 1 (STAT1)-activated gene expression. The Journal of biological chemistry. 2011;286(48): 41195-204. PMID: 22002246 | PMCID: PMC3308833
  • Buro L, Chipumuro E, Henriksen M. Menin and RNF20 recruitment is associated with dynamic histone modifications that regulate signal transducer and activator of transcription 1 (STAT1)-activated transcription of the interferon regulatory factor 1 gene (IRF1). Epigenetics & chromatin. 2010;3(1): 16. PMID: 20825659 | PMCID: PMC2940767
  • Buro L, Shah S, Henriksen M. Chromatin immunoprecipitation (ChIP) to assay dynamic histone modification in activated gene expression in human cells. Journal of visualized experiments : JoVE. 2010;. PMID: 20729799 | PMCID: PMC3156077
  • Buro L, Chipumuro E, Henriksen M. Menin and RNF20 recruitment is associated with dynamic histone modifications that regulate signal transducer and activator of transcription 1 (STAT1)-activated transcription of the interferon regulatory factor 1 gene (IRF1). Epigenetics Chromatin. 3(1): 16.0. PMCID: PMC2940767