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Projects

Pfeifer Laboratory

DNA methylation and cancer

One of the lab’s primary projects is studying the mechanisms and biological significance of CpG island hypermethylation by investigating the molecular pathways that lead to DNA methylation changes in tumors. The lab’s hypothesis is that specific factors such as carcinogenic agents, oncogene activation leading to epigenetic changes, inflammation, mechanisms related to the Polycomb repression complex, and imbalances between methylation and demethylation pathways drive CpG island methylation in tumors.

The role of 5-hydroxymethylcytosine (5hmC) in development and disease

The lab’s model proposes that 5hmC is an intermediate in DNA demethylation, while other data suggests 5hmC is a stable DNA modification. This question still is being investigated.

The Pfeifer lab has previously found that 5hmC is extremely rare in human cancer; therefore, this knowledge could lead to new biomarkers for malignant cancer. The lab hypothesizes that defects in 5-methylcytosine (5mC) oxidation are responsible for different DNA methylation patterns in tumors and, potentially, other diseases. To test this hypothesis, the Pfeifer lab has established and used methodology for genome-wide mapping and precise quantification of 5mC and 5hmC, with the goal of determining genomic distribution of 5hmC in normal tissue and in malignant tumors. To this end, the lab focuses on solid tumors, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) as these cancers are characterized by mutations in the TET2 gene, which produces an enzyme that catalyzes the conversion of 5mC to 5hmC. The lab conducts basic mechanistic studies of TET and TET-associated proteins, along with their regulation, abnormalities in cancer and their roles in cell differentiation and CpG island integrity.

RASSF1 and the Hippo pathway

The Pfeifer lab had previously identified the gene RASSF1A, which undergoes methylation silencing in the majority of human tumors. The RASSF1A pathway shows the importance of epigenetic silencing in the absence of frequent gene mutation. The Pfeifer lab has also shown that RASSF1A is an upstream regulator of the Hippo tumor suppressor pathway. The lab continues to study the biochemical function of RASSF1A and related genes in the Hippo pathway.

Aging and epigenomic instabilities

The Pfeifer lab is interested in studying if and how epigenomic changes contribute to aging by analyzing a range of epigenetic marks, including DNA CpG methylation and chromatin modification, in vitro and in vivo.