Tahiliani Lab Research
Researchers in the Tahiliani Lab investigate the mechanisms that shape the unique DNA methylation patterns found in different cell types. These patterns are established early in development and are propagated through cell division by a maintenance mechanism.
We discovered that the cancer-associated TET proteins convert 5-methylcytosine (5mC) in DNA to the novel base 5-hydroxymethylcytosine (5hmC). It is now known that TET enzymes can diversify the epigenetic content of DNA tremendously and can also trigger DNA demethylation. These studies have revealed that DNA methylation patterns are much more dynamic then previously assumed. Disrupted patterns are seen in cancer, aging, and developmental disorders, where they are associated with genomic instability.
We are currently interested in two broad questions.
What Are the Molecular Mechanisms Underlying the Maintenance of DNA Methylation Patterns and How Are These Mechanisms Perturbed in Disease?
Both primary tumors and cancer cell lines frequently exhibit hypermethylation of promoters on a background of global hypomethylation. Although hypomethylation of the genome correlates strongly with increased malignancy, most research has focused on aberrant promoter methylation and the concomitant silencing of tumor suppressor genes. Hypomethylation is associated with increased chromosomal rearrangements and mutation rates, events well known to drive tumor evolution.
We propose that hypomethylation of DNA is a key distinction between normal and tumor cells that can be selectively targeted in the clinic. We are taking both unbiased and candidate approaches to identify genes involved in establishing and maintaining DNA methylation patterns. We hypothesize that drugs that restore normal methylation will suppress DNA damage that underlies malignant progression and will provide a viable strategy for targeting many types of tumors.
How Does DNA Methylation Preserve Genomic Stability?
Although it is well established that the genome-wide hypomethylation frequently seen in tumors is strongly associated with malignancy, a direct role for hypomethylation in tumorigenesis has not yet been demonstrated. In support of a direct link, hypomethylation of the genome is associated with DNA damage and increased chromosomal rearrangements, events well known to drive tumorigenesis. The mutations and rearrangements observed in hypomethylated cells are most pronounced at regions enriched in repetitive elements and require DNA synthesis to occur, indicating that impediments to DNA replication may play a role in the instability observed in incipient tumor cells. We aim to uncover the mechanism by which DNA methylation influences replication and repair of the genome and thus protects against the development of cancer.