Stable inheritance of epigenetic states is essential for the maintenance of tissue and cell type specific functions. Aberrations of epigenetic regulation often lead to cancer and other human diseases. Our laboratory is interested in epigenetic regulation by histone demethylases in cancer and stem cells. In particular, we focus on the roles and regulatory mechanisms of histone demethylases from the JARID1/KDM5 protein family (Figure 1). These enzymes can remove tri- and di- methyl mark from lysine 4 in histone H3 (H3K4me3 and H3K4me2) (figure 1), the epigenetic marks for transcriptionally active chromatin.
We have previously identified RBP2 (Retinoblastoma Binding Protein 2, also known as JARID1A or KDM5A) as one of the first known histone demethylases for H3K4me3. To understand the in vivo function of this enzyme, we generated an Rbp2-/- mouse model (Figure 2), which is the first knockout mouse model for lysine demethylases. We have further showed that RBP2 is critical for tumor formation in several genetically engineered mouse cancer models. We are currently studying how this enzyme contributes to oncogenesis using highly integrated mouse genetic, molecular and cellular biological, and biochemical (Figure 3) approaches. Its functions will be better understood if we combine our findings at the organismal, cellular and molecular levels.
The other research directions of our laboratory focus on another H3K4me3 histone demethylase JARID1B (also known as PLU1 or KDM5B). JARID1B is highly expressed in breast and prostate tumors and is a marker of slow cycling and drug resistant melanoma cells. Similar approaches are undertaken to investigate its roles in cancer. Our current data suggest that these enzymes are potential drug targets for cancer therapy and we have identified specific inhibitors of these enzymes.
Figure 1. The JARID1/KDM5 proteins are histone demethylases for H3K4me3 and H3K4me2.
Figure 2. Generation of an Rbp2-/- mouse model
Figure 3. Isolation of the histone demethylase complexes using FLAG and biotin tags.
The red flag denotes the FLAG tag, and the yellow circle with B denotes the biotin tag.