Areas of Interest
Epigenetics refers to heritable changes that are not encoded in the DNA sequence. It has emerged that histones, the basic building blocks of the hierarchical chromatin structure in eukaryotes, are major carriers of epigenetic information. Numerous and often evolutionarily conserved covalent modifications of histones play important roles in regulating gene transcription, cell cycle progression, DNA damage repair, DNA as well as organism development. Recent studies show that many epigenetic enzymes are frequently mutated or silenced in human malignancies. Epigenetic diagnostic and therapy are now entering clinical phase.
Our broad objectives are to study the chromatin modifying enzymes that catalyze histone lysine methylation, acetylation and ubiquitylation and develop inhibitory molecular probes that allow for functional studies. We are currently studying the regulation of the MLL/SET1 family histone H3 lysine 4 methyltransferases and MYST family histone acetyltransferase MOF, two enzymes that function coordinately in transcription activation. We are also characterizing the molecular mechanisms of how these enzymes contribute to malignant processes in vivo.
Honors & Awards
2014 Dean’s award in Basic Science
2012 Leukemia & Lymphoma Society Scholar Award
2011 Stand Up to Cancer IRG Award
2010 AACR Gertrude B. Elion Cancer Research Award
2010 American Cancer Society RSG Award
2007 Biomedical Science Scholar, University of Michigan
Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J, Allis CD, Chait BT, Hess JL, Roeder RG: Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121(6): 873-885, 2005.
Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG: Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat. Struct. Mol. Biol. 13(8): 713-719, 2006.
Li X, Wu L, Corsa CA, Kunkel S, Dou Y: Two mammalian MOF complexes regulate transcription activation by distinct mechanisms. Molecular Cell, 36 (2): 290-301, 2009.
Wu L, Zee BM, Wang Y, Garcia BA, Dou Y: The RING Finger Protein MSL2 in the MOF Complex Is an E3 Ubiquitin Ligase for H2B K34 and Is Involved in Crosstalk with H3 K4 and K79 Methylation. Molecular Cell, 43(1): 132-144, 2011.
Chen Y, Wan B, Wang KC, Cao F, Yang Y, Protacio A, Dou Y, Chang HY, Lei M: Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA binding. EMBO Rep. 12(8): 797-803, 2011.
Chen Y, Cao F, Wan B, Dou Y, Lei M: Structure of the SPRY domain of human Ash2L and its interactions with RbBP5 and DPY30. Cell Res. 22(3): 598-602, 2012.
Huang J, Wan B, Wu L, Yang Y, Dou Y, Lei M: Structural insight into the regulation of MOF in the male-specific lethal complex and the non-specific lethal complex. Cell Res. 22(6): 1078-1081, 2012.
Li X, Li L, Pandey R, Byun JS, Gardner K, Qin Z, Dou Y: The Histone Acetyltransferase MOF Is a Key Regulator of the Embryonic Stem Cell Core Transcriptional Network. Cell Stem Cell, 11(2): 163-178, 2012.
Karatas H, Townsend EC, Cao F, Chen Y, Bernard D, Liu L, Lei M, Dou Y, Wang S: High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein-Protein Interaction. J. Am. Chem. Soc., 135(2): 669-682, 2013.
Pandey R, Dou Y: H2A.Z sets the stage in ESCs. Cell Stem Cell 12(2): 143-144, 2013.
Wu L, Lee SY, Zhou B, Nguyen UT, Muir TW, Tan S, Dou Y: ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes. Molecular Cell, 49 (6): 1108-1120, 2013.
Cao F, Townsend EC, Karatas H, Xu J, Li L, Lee S, Liu L, Chen Y, Ouillette P, Zhu J, Hess JL, Atadja P, Lei M, Qin ZS, Malek S, Wang S, Dou Y: Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Molecular cell, 53 (2): 247-61, 2014.
Wu L, Li L, Qin Z and Dou Y: MSL2 mediated H2B K34 ubiquitylation promotes RNA Pol II processivity through regulating PAF1 and pTEFb pathways. Molecular Cell, 54 (6): 920-931, 2014