Gene Expression Regulation; Neoplasm Metastasis; Neoplasms; Stem Cells; Neoplastic Stem Cells; Histone Demethylases; Epigenomics
Discovery to Cure Internship
Stem Cell Center, Yale: Transcriptional Regulation of Stem and Progenitor Cells
Epigenetic aberrations often lead to cancer and other human diseases. Our laboratory is interested in dissecting the roles of epigenetic regulators in cancer and stem cells. In particular, we focus on the roles and regulatory mechanisms of histone demethylases for tri- methylated lysine 4 in histone H3 (H3K4me3), the epigenetic mark for transcriptionally active chromatin. We have previously showed RBP2/JARID1A is one of the first known histone demethylases for H3K4me3. Using the RBP2 knockout mouse model, we further showed that loss of RBP2 inhibits tumorigenesis in several genetically-engineered mouse models. We are currently studying how this enzyme contributes to oncogenesis using a combination of biochemical, molecular biological, cell biological and mouse genetic approaches. We are also investigating the roles of another H3K4me3 histone demethylase PLU1/JARID1B. These enzymes are potential drug targets for epigenetic therapies against cancer, and we have developed first generation inhibitors against these enzymes.
Specialized Terms: Epigenetics; Gene regulation; Cancer biology; Stem cell biology
- Cao J, Wu L, Zhang SM, Lu M, Cheung WK, Cai W, Gale M, Xu Q, Yan Q. An easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targeting. Nucleic Acids Res. 2016 Jul 25. pii: gkw660
- Horton JR, Liu X, Gale M, Wu L, Shanks JR, Zhang X, Webber PJ, Bell JS, Kales SC, Mott BT, Rai G, Jansen DJ, Henderson MJ, Urban DJ, Hall MD, Simeonov A, Maloney DJ, Johns MA, Fu H, Jadhav A, Vertino PM, Yan Q#, Cheng X#. Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds. Cell Chem Biol. 2016;23:769-81 # co-corresponding authors
- Cao J, Liu Z, Cheung WKC, Zhao M, Chen SY, Chan SW, Booth CJ, Nguyen DX, Yan Q. Histone demethylase RBP2 is critical for breast cancer progression and metastasis, Cell Reports, 2014; 6(5):868-77
- Cao J and Yan Q. Histone Demethylases Set the Stage for Cancer Metastasis. Science Signaling. 2013; 6:pe15.
- Sayegh J, Cao J, Zou MR, Morales A, Blair LP, Norcia M, Hoyer D, Tackett AJ, Merkel J, Yan Q. Identification of Small Molecule Inhibitors of Jumonji AT-Rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen. J Biol Chem. 2013 Mar 29;288(13):9408-17.
- Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y, Francis J, Cherniack AD, Geisen C, Blair LP, Zou MR, Shen X, Kawamori D, Liu Z, Grisanzio C, Watanabe H, Minamishima YA, Zhang Q, Kulkarni RN, Signoretti S, Rodig SJ, Bronson RT, Orkin SH, Tuck DP, Benevolenskaya EV, Meyerson M, Kaelin WG Jr, Yan Q. Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc Natl Acad Sci U S A. 2011;108:13379-86.
- 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. 2007; 128:889-900 *equal contribution