Mei-Yi Wu, PhD

I graduated from National Yang-Ming College of Medicine, Taiwan with a Ph.D. in immunology. My PhD training was in study of the signal transduction pathway of tumor necrosis factor receptor superfamily member 3 (TNFRSF3) that mediates cell death. As TNFRSF3 lacks inherent enzymatic activity, we investigated the signal pathway of TNFRSF3 through identifying its associated proteins. We provided evidence that two serine/threonine kinases associate with TNFRSF3 and further phosphorylate this receptor. Our study presented novel signal transduction of the TNFR pathway.

My postdoctoral training was in Dr. Arthur L. Beaudet’s laboratory at the Department of Molecular and Human Genetics at Baylor College of Medicine. I studied knockout mice as animal models for human diseases. In Dr. Beaudet’s lab, we generated the conventional knockout mice carrying the Arid4a and Arid4b mutations. Using these mouse models, we have published the important findings describing mouse models for imprinting diseases Prader-Willi syndrome and Angelman syndrome and tumor suppression for leukemia malignancies. In 2006, I was promoted to Research Assistant Professor.

I relocated to the George Washington University as an Assistant Research Professor in 2010, and was promoted to Associate Research Professor in 2017. I continued to work on the Arid4a and Arid4b knockout mouse models of human diseases. While the conventional Arid4a knockout (Arid4a^-/-) mice are viable, the conventional Arid4b knockout (Arid4b^-/-) mice are embryonic lethal. To overcome embryonic lethality and investigate the function of Arid4b in specific tissue, we generated the conditional Arid4b knockout mouse model. Besides the roles on the imprinting diseases, we found that Arid4a and Arid4b are important for prostate cancer development and male reproductive function. To investigate the mechanisms, we found ARID4A and ARID4B function as androgen receptor co-activators.

In 2023, I joined the Department of Biochemistry and Molecular Biology at the University of Maryland School of Medicine as an Assistant Professor in the tenure track.

My laboratory studies the roles of the chromatin remodeling protein, AT-rich interaction domain 4B (ARID4B), in human diseases, including development disorders and cancers. Epigenetic changes are important for human diseases. Disruption of epigenetic modification leads to dysregulation of gene function without altering the DNA sequence. Therefore, epigenetic modification is a reversible process, a characteristic that other treatments may not offer. Chromatin remodeling proteins are responsible for the dynamic epigenetic modifications of chromatins that allow transcription machinery proteins gaining access to genomic DNA, and thereby control gene expression. Chromatin modifications impart epigenetic regulation in biological development. Abnormal chromatin modifications are associated with human developmental disorders and cancers. Targeting chromatin remodeling pathways can be a major therapeutic strategy in the treatment of these diseases.

In cancer research, we study breast cancer and prostate cancer, focusing on ARID4B oncogenic function in (1) therapeutic resistance in breast cancer, (2) tumorigenesis and castration resistance in prostate cancer, and (3) discovery of small molecule compounds that inhibit ARID4B. In development research, we study the central nervous system disorders and kidney formation, focusing on ARID4B function in (1) neurodegeneration in the central nervous system and (2) nephron patterning during kidney development.

Using the cell culture system (in vitro), genetically engineered mouse models and xenograft mouse models (in vivo), and bioinformatic approach, we study the biological function of ARID4B in human diseases and investigate the underlying molecular mechanisms of disorders. The functional and molecular characterization will provide the mechanisms linking diseases, leading to potential therapeutic approaches. Therefore, we further rescue the disorders using pharmacological approaches and preclinical mouse models.

Epigenetics, Chromatin remodeling protein, Breast cancer, Prostate Cancer, Kidney development, Neurodegeneration

Young I.C., Wu B., Andricovich J., Chuang S.T., Li R., Tzatsos A., Wu R.C., and Wu M.Y. (2021) Differentiation of fetal hematopoietic stem cells requires ARID4B to restrict autocrine KITLG/KIT-Src signaling. Cell Reports. 37(8):110036. PMID: 34818550.

Wu R.C., Young I.C., Chen Y.F., Chuang S.T., Toubaji A., and Wu M.Y. (2019). Identification of the PTEN-ARID4B-PI3K pathway reveals the dependency on ARID4B by PTEN-deficient prostate cancer. Nat Commun 10, 4332. PMID: 31551414.

Wu R.C., Zeng Y., Chen Y.F., Lanz R.B., and Wu M.Y. (2017). Temporal-spatial establishment of initial niche for the primary spermatogonial stem cell formation is determined by an ARID4B regulatory network. Stem Cells. Jun;35(6):1554-1565. PMID: 28207192.

Wu M.Y. and Wu R.C. Unfolded Protein Response and Cancer. Encyclopedia of Cancer, Third Edition, Dr. Manfred Schwab (ed.) (2016).

Wu M.Y. and Wu R.C. (2016) A Sensitive and Flexible Assay for Determining HDAC1 Activity. Methods in Molecular Biolog. 1436:3-13. PMID: 27246204.

Wu R.C., Zeng Y., and Wu M.Y. (2015) AR Coactivator ARID4B is Required for the Function of Sertoli Cells in Spermatogenesis. Mol Endocrinol. 29(9):1334-46. PMID: 26258622.

Wu M.Y., Fu J, Xiao X, Wu J, Wu R.C. (2014) MiR-34a regulates therapy resistance by targeting HDAC1 and HDAC7 in breast cancer. Cancer Letters. 354(2):311-9. PMID: 25173798.

Wu R.C., Jiang M., Beaudet A.L., and Wu M.Y. (2013) ARID4A and ARID4B regulate male fertility, a functional link to the AR and RB pathways. Proc Natl Acad Sci U S A. 110(12):4616-21. PMID: 23487765. (Highlighted by Biology of Reproduction).

Wu M.Y., Fu J., Xu J., O’Malley B.W., and Wu R.C. (2012b) Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor. Cell Research 22:1003-21. PMID: 22430150. PMCID: PMC3367527.

Wu M.Y., Jiang M., Zhai X., Beaudet A.L., and Wu R.C. (2012a) An unexpected function of the Prader-Willi syndrome imprinting center in maternal imprinting in mice. PLoS ONE 7(3): e34348. PMID: 22496793. PMCID: PMC3319576.

Wu M.Y., Eldin K., and Beaudet A.L. (2008) Chromatin remodeling genes Arid4a and Arid4b function as leukemia suppressor genes. J Natl Cancer Inst 100(17):1247-59. PMID: 18728284. PMCID: PMC2528019.

Wu M.Y., Tsai T.F., and Beaudet A.L. (2006) Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain. Genes Dev. 20(20):2859-70. PMID: 17043311.

Wu M.Y., Chen K.S., Bressler, J., Hou A., Tsai T.F., and Beaudet A.L. (2006) Mouse imprinting defect mutations that model Angelman syndrome. Genesis 44(1):12-22. PMID: 16397868.

Bressler J., Tsai, T.F., Wu M.Y., Tsai S.F., Ramirez M.A., Armstrong D., and Beaudet A.L. (2001) The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice. Nature Genetics 28(3):232-40. PMID: 11431693.

Wu M.Y., Wang P.Y., Han S.H. and Hsieh S.L. (1999) The cytoplasmic domain of lymphotoxin- β receptor mediates cell death in HeLa cells. J. Biol. Chem. 274(17):11868-11873. PMID: 10207006.

Wu M.Y., Hsu T.L., Lin W.W., Capmbell R.D., and Hsieh S.L. (1997) Serine/threonine kinase activity associated with the cytoplasmic domain of lymphotoxin-β receptor in HepG2 cells. J. Biol. Chem. 272(27):17154-9. PMID: 9202035.