Research
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 (Fig. 1) in cancer and stem cells. In particular, we focus on the roles and regulatory mechanisms of histone demethylases from the JARID1/KDM5 protein family (Fig. 2). These enzymes can remove tri- and di- methyl mark from lysine 4 in histone H3 (H3K4me3 and H3K4me2) (Fig. 2), the epigenetic marks for transcriptionally active chromatin.
We have previously identified RBP2 (Retinoblastoma Binding Protein 2) 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 (Fig. 3), which is the first knockout mouse model for lysine demethylases. We are currently studying how this enzyme contributes to oncogenesis using highly integrated mouse genetic (Fig. 3), molecular and cellular biological (Fig. 4), and biochemical (Fig. 5) 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 PLU-1. PLU-1 is highly expressed in breast and prostate cancer samples. Knockdown of PLU-1 expression in breast cancer cells impairs their ability to form breast tumors in xenograft mouse model. Similar approaches are undertaken to investigate its roles in cancer. Our current data suggest that these enzymes are potential drug targets for cancer therapy.
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People
Current members of the Yan laboratory:
- Lauren Blair, PhD, Postdoctoral Associate, email: lauren.blair@yale.edu
- Jian Cao, PhD, Postdoctoral Associate, email: jian.cao@yale.edu
- Mike Zou, Graduate Student, email: ran.zou@yale.edu
Lab alumni:
Amber Anders, Yale Biostep program student
Christine Phan, Yale Discovery to Cure program student
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Publications
Selected Publications:
Oevelen CV, Wang J, Asp P, Yan Q, Kaelin WG, Kluger Y, Dynlacht BD. A role for mammalian Sin3 in permanent gene silencing. Mol Cell 32:359-70 (2008)
Klose RJ*, Yan Q*, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, Gilliland DG, Zhang Y, Kaelin WG. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128:889-900 (2007) *equal contribution
Yang H, Minamishima YA, Yan Q, Schlisio S, Ebert BL, Zhang X, Zhang L, Kim WY, Olumi AF, Kaelin WG. pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kB agonist Card9 by CK2. Mol Cell 28:15-27 (2007)
Li L, Zhang L, Zhang X, Yan Q, Minamishima YA, Olumi A, Mao M, Bartz S, Kaelin WG. HIF linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol Cell Biol., 27:5381-92 (2007)
Yan Q, Bartz S, Mao M, Li L, Kaelin WG. The HIF2 alpha N-terminal and C-terminal transactivation domains cooperate to promote renal tumorigenesis in vivo. Mol Cell Biol. 27:2092-102 (2007)
Yan Q, Kamura T, Cai Y, Jin J, Ivan M, Mushegian A, Conaway RC, Conaway JW. Identification of Elongin C and Skp1 sequences that determine cullin selection. J. Biol. Chem. 279:43019-26 (2004)
Blanchette P, Cheng CY, Yan Q, Ketner G, Ornelles DA, Dobner T, Conaway RC, Conaway JW, Branton PE. Both BC-box motifs of adenovirus protein E4orf6 are required to efficiently assemble an E3 ligase complex that degrades p53. Mol Cell Biol. 24:9619-29 (2004)
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