Wen Laboratory

Epigenetics and Transcription

Alterations in epigenetic landscape, together with genetic changes, are key events in initiation, progression and drug resistance of human cancers. The Wen Laboratory’s goal is to delineate how cancer cells, particularly pediatric cancers, exploit chromatin machinery to activate oncogenic or silent tumor suppressive gene expression programs, with the long-term goal of developing therapies to target epigenomic or epigenetic regulators for cancer treatment.

One of the lab’s current research projects is to characterize the role of ENL/MLLT1 in MLL-rearranged leukemia and other pediatric cancers. MLL-rearranged leukemia is a subtype of acute leukemia caused by MLL gene translocation, which accounts for about 70 percent of pediatric leukemia cases. Their previous work has identified the YEATS domain as a novel reader of histone acetylation (Li and Wen et al, Cell 2014) and uncovered that the ENL YEATS domain is critical for the expression of essential genes for disease maintenance in MLL-rearranged leukemia (Wan and Wen et al, Nature 2017). The lab is currently characterizing the role of ENL and its YEATS domain in tumor initiation and maintenance in a broad range of pediatric leukemias. We are also working on development of small molecules targeting the YEATS domain of ENL.

The ENL YEATS domain is frequently mutated in Wilms tumor, the most common pediatric kidney cancer. Another of the lab’s project is to investigate the molecular mechanism by which the ENL mutations contribute to Wilms tumor oncogenesis.

Dr. Wen and her team also study tumor suppressor ZMYND11, an adenovirus E1A-binding protein. She has previously identified that ZMYND11 is a bona-fide histone variant H3.3-specific reader of H3K36 methylation that regulates transcription elongation (Wen et al, Nature 2014).  Her lab is now generating a knockout mouse model to determine the role of ZMYND11 in tumor suppression in vivo.

Xue Z*, Qin L*, Xuan H*, Luo K*, Huang M, Xie L, Su Y, Xu L, Harsh J, Dale B, Shi X, Chen X, Kaniskan JÜ, Jin J#, Wen H#. 2024.  A potent and selective ENL degrader suppresses oncogenic gene expression and leukemia progression. Sci Adv 10(35).
# Co-corresponding authors

Abla O, Ries RE, Triche Jr TJ, Gerbing RB, Hirsch B, Raimondi S, Cooper TM, Farrar JE, Buteyn N, Harmon LM, Wen H, Deshpande AJ, Kolb EA, Gamis AS, Aplenc R, Alonzo T, Meshinchi S. 2024. Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia. Blood Adv.

Xu L, Xuan H, He W, Zhang L, Huang M, Li K, Wen H, Xu H, Shi X. 2023. TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition. Nat Commun. 14(1):5362.

Tencer AH, Yu Y, Causse SZ, Campbell GR, Klein BJ, Xuan H, Cartier J, Miles MA, Gaurav N, Zadoroznyj A, Holt TA, Wen H, Hawkins CJ, Spector SA, Dubrez L, Shi X, Kutateladze TG. 2023. Molecular basis for nuclear accumulation and targeting of the inhibitor of apoptosis BIRC2. Nat Struct Mol Biol. 30(9):1265-1274.

Ma XR^*, Xu L^*, Xu S, Klein BJ, Wang H, Das S, Li K, Yang KS, Sohail S, Chapman A, Kutateladze TG, Shi X, Liu WR^#, Wen H^#. 2021. Discovery of selective small-molecule inhibitors for the ENL YEATS domain.  J Med Chem 64(15):10997-11013.

Klein BJ, Deshpande A, Cox KL, Xuan F, Zandian M, Barbosa K, Khanal S, Tong Q, Zhang Y, Zhang P, Sinha A, Bohlander SK, Shi X, Wen H, Poirier MG, Deshpande AJ, Kutateladze TG. 2021. The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations. Nat Commun 12(1):4130.

Yu Y, Wen H, Shi X. 2021. Histone mimics: more tales to read.  Biochem J 478(14):2789-2791.

Wen H, Shi X. 2020. H3.3S31 phosphorylation: linking transcription elongation to stimulation responses. Signal Transduct Target Ther 5(1):176.

Wan L^#, Chong S^*, Xuan F^*, Liang A^*, Cui X, Gates L, Carroll TS, Li Y, Feng L, Chen G, Wang SP, Ortiz WV, Saley SK, Wang X, Xuan H, Kentsis A, Muir TW, Roeder RG, Li H, Li W, Tijan R, Wen H^#, Allis CD^#. 2020. Impaired cell fate through gain-of-function mutations in a chromatin reader. Nature 577:121–126.
*Equal contribution
#Co-correspondence

Mi W, Zhang Y, Lyu J, Wang X, Tong Q, Peng D, Xue Y, Tencer AH, Wen H, Li W, Kutateladze TG, Shi X. 2018. The ZZ-type zinc finger of ZZZ3 modulates the ATAC complex-mediated histone acetylation and gene activation. Nat Commun 9(1):3759.

Zhang Y, Xue Y, Shi J, Ahn J, Mi W, Ali M, Wang X, Klein BJ, Wen H, Li W, Shi X, Kutateladze TG. 2018. The ZZ domain of p300 mediates specificity of the adjacent HAT domain for histone H3.
Nat Struct Mol Biol 25(9):841-849.

Shi L*, Shi J*, X S, Li W, Wen H. 2018. Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis. J Mol Biol. pii:S0022-2836(18)30248-1.

Hsu C, Shi J, Yuan C, Zhao D, Jiang S, Lyu J, Wang X, Li H, Wen H, Li W, Shi X. 2018. Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer. Genes Dev 32(1):58–69.

Wan L*, Wen H*, Li Y*, Lyu J, Xi Y, Hoshii T, Joseph J, Wang X, Loh Y, Souza AL, Bradner JE, Shen L, Li W, Li H, Allis CD, Armstrong SA, Shi X. 2017. ENL links histone acetylation to oncogenic gene expression in AML. Nature 543(7644):265–269.
*Equal contribution

Mi W, Guan H, Lyu J, Zhao D, Xi Y, Jiang S, Andrews FH, Wang X, Gagea M, Wen H, Tora L, Dent SYR, Kutateladze TG, Li W, Li H, Shi X. 2017. YEATS2 links histone acetylation to tumorigenesis of non-small cell lung cancer. Nat Commun 8(1):1088.

Shi L, Wen H, Shi X. 2016. The histone variant H3.3 in transcriptional regulation and human disease. J Mol Biol 429(13):1934–1945.

Li N, Li Y, Lv J, Zheng X, Wen H, Shen H, Zhu G, Chen TY, Dhar SS, Kan PY, Wang Z, Shiekhattar R, Shi X, Lan F, Chen K, Li W, Li H, Lee MG. 2016. ZMYND8 reads the dual histone mark H3K4me1-H3K14ac to antagonize the expression of metastasis-linked genes. Mol Cell 63(3):470–484.

Zhang X, Peng D, Xi Y, Yuan C, Sagum CA, Klein BJ, Tanaka K, Wen H, Kutateladze TG, Li W, Bedford MT, Shi X. 2016. G9a-mediated methylation of ERα links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression. Nature Commun 7:10810.

Zhao D, Guan H, Zhao S, Mi W, Wen H, Li Y, Zhao Y, Allis CD, Shi X, Li H. 2016. YEATS2 is a selective histone crotonylation reader. Cell Res 26(5):629–632.

Li Y*, Wen H*, Xi Y, Tanaka K, Wang H, Peng D, Ren Y, Jin Q, Dent SR, Li W, Li H, Shi X. 2014. AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell 159(3):558–571.
*Equal contribution

Wen H*^{, #}, Li Y*, Xi Y*, Jiang S, Stratton S, Peng D, Tanaka K, Ren Y, Xia Z, Wu J, Li B, Barton MC, Li W^#, Li H^#, Shi X^#. 2014. ZMYND11 links histone H3.3 K36 trimethylation to transcription elongation and tumor suppression. Nature 508(7495):263–268.
*Equal contribution
^#Co-correspondence

Guo R, Zheng L, Park JW, Lv R, Chen H, Jiao F, Xu W, Mu S, Wen H, Qiu J, Wang Z, Yang P, Wu F, Hui J, Fu X, Shi X, Shi YG, Xing Y, Lan F, Shi Y. 2014. BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing. Mol Cell 56(2):298–310.

Klein BJ, Piao L, Xi Y, Rincon-Arano H, Rothbart SB, Peng D, Wen H, Larson C, Zheng X, Cortazar M, Peña PV, Mangan A, Bentley DL, Strahl BD, Groudine M, Li W, Shi X and Kutateladze T. 2014. The histone-H3K4-specific demethylase KDM5B binds to its substrate and product through distinct PHD fingers. Cell Rep 6(2):325–335.

Wen H, Li Y, Li H, Shi X. 2014. ZMYND11: An H3.3-specific reader of H3K36me3. Cell Cycle 13(14):2153–2154.

Zhang X, Tanaka K, Yan J, Li J, Peng D, Jiang Y, Yang Z, Barton MC, Wen H, Shi X. 2013. Regulation of estrogen receptor α by histone methyltransferase SMYD2-mediated protein methylation. Proc Natl Acad Sci USA 110(43):17284–17289.

DeBruhl H, Wen H, Lipsick JS. 2013. The complex containing Drosophila Myb and RB/E2F2 regulates cytokinesis in a histone H2Av-dependent manner. Mol Cell Biol 33(9):1809–1818.

Andrejka L*, Wen H*, Ashton J, Grant M, Iori K, Wang A, Manak JR, Lipsick JS. 2011. An animal-specific C-terminal domain links Myb to the ancient MuvB repressor complex. Proc Natl Acad Sci USA 108(42):17438–17443.
*Equal contribution

Wen H*, Li J*, Song T*, Lu M, Kan PY, Lee MG, Sha B, Shi X. 2010. Recognition of histone H3K4 trimethylation by the PHD finger of PHF2 modulates histone demethylation. J Biol Chem 285(13):9322–9926. *Equal contribution

Wen H, Andrejka L, Ashton J, Karess R, Lipsick JS. 2008. Epigenetic regulation of gene expression by Drosophila Myb and E2F2-RBF via the Myb- MuvB/dREAM complex. Genes Dev 22:601–614.

Shi X, Kachirskaia I, Yamaguchi H, West LE, Wen H, Wang EW, Dutta S, Appella E, Gozani O. 2007. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol Cell 27(4):636–646.

Manak JR, Wen H, Van T, Andrejka L, Lipsick JS. 2007. Loss of Drosophila Myb interrupts the progression of chromosome condensation. Nat Cell Biol 9:581–587.

Wang DM, Sevcikova S, Wen H, Roberts S, Lipsick JS. 2007. v-Myb represses the transcription of Ets-2. Oncogene 26:1238-1244.