- Assistant Professor
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX US
- PhD from University of Chinese Academy of Sciences
- 08/2008 - Beijing, Beijing China
- Postdoctoral Training at Yale Stem Cell Center, Yale School of Medicine
- New Haven, United States
- Deciphering the Driver Epigenetic Mutations in Cancer
- Understanding the Dynamics of Epigenetic Regulation
- Overcoming the Cancer Treatment Resistance
Professional StatementThe core question we want to answer is how the epigenetic factors dynamically regulate the cell fate decision and the response to external stimulation, specifically underlying cancer therapeutic resistance. Our final goal is to apply the fundamental knowledge for curing human diseases. Cancer is a systems biological disease. The tumor is a complex and robust biological system. Although we have developed powerful weapons such as chemotherapies, molecularly targeted therapies and immunotherapies to kill cancer cells, cancer treatment resistance is still a pressing challenge in current cancer research and treatment. Although acquired resistance can be developed by genetic mutations of tumor cells during treatment, it could also be due to many non-genetic factors such as activation of compensatory signaling pathways or stimuli-response epigenetic regulatory processes. Epigenetic regulatory processes in mammals, such as DNA methylations and histone modifications, are pivotal for controlling cellular functions. The profound alterations of DNA methylation (5mC) and histone modifications are common signatures in most types of cancer. Meanwhile, vast efforts were devoted to developing the drugs or small molecules by targeting epigenetic regulators, which can manipulate epigenomic modifications (such as HDACs for H3K27ac or DNMTs for DNA 5mC) in cancer cells to alter the activity of the responsive genes. However, the underlying molecular mechanisms of cancer epigenetics are still elusive.
In previous work, I discovered a novel DNA modification “N6-methyladenine” (6mA, DNA methylation that had never been identified in mammals before) with SMRT-ChIP (3rd-generation single-molecule real-time sequencing with native ChIP samples) in mouse embryonic stem cells. We also identified ALKBH1 as the major demethylase of DNA 6mA. In 2018, we pinpointed that the 6mA is elevated in glioblastoma stem cells and high-grade glioblastoma (GBM) patient samples. In contrast, the 6mA’s abundance is much lower in the non-stem-like GBM cells or low-grade GBM patient’s samples. Furthermore, the demethylase ALKBH1 appears to regulate hypoxia response genes which were well-known for driving the drug resistance in GBM. Based on these discoveries, we hypothesize that DNA 6mA might be a driver epigenetic mutation and its regulators could constitute an essential pathway that manipulates cancer therapeutic resistance. The DNA 6mA’s readers, writers or erasers, could be novel targets that could be targeted to bypass the resistance and boost the current therapies.
In our lab, we focus on the research projects to explore novel epigenetic regulatory processes and identify new epigenomic targets of the treatment-resistant cancerous cells with holistic approaches (genomics, genetics, biochemistry, systems biology and high-throughput screening). With the adapted single-molecule SMRT sequencing, single-cell sequencing and customized CRISPR/Cas9 screening approaches, we will explore new epigenetic players in cancer model systems.
- Li X, Guo S, Cui Y, Zhang Z, Luo X, Angelova MT, Landweber LF, Wang Y, Wu TP "NT-seq: a chemical-based sequencing method for genomic methylome profiling." Genome Biol.. 2022 May;23:122. Pubmed PMID: 35637459
- Li Z*, Zhao S*, Nelakanti RV*, Lin K*, Wu TP*, et al. "N6-methyladenine in DNA antagonizes SATB1 in early development.." Nature. 2020;583:625-630. Pubmed PMID: 32669713
- Xie Q*, Wu TP*, Gimple RC*, et al "N(6)-methyladenine DNA Modification in Glioblastoma." Cell. 2018 Oct 30;175:1228-1243.e20. Pubmed PMID: 30392959
- Wu TP, Wang T, et al "DNA methylation on N(6)-adenine in mammalian embryonic stem cells.." Nature. 2016;532:329-33. Pubmed PMID: 27027282
- Zhu S, Beaulaurier J, Deikus G, Wu TP, et al "Mapping and characterizing N6-methyladenine in eukaryotic genomes using single-molecule real-time sequencing." Genome Res. 2018;28:1067-1078.
- Benchetrit H, Herman S, van Wietmarschen N, Wu T, et al "Extensive Nuclear Reprogramming Underlies Lineage Conversion into Functional Trophoblast Stem-like Cells." Cell Stem Cell. 2015;17:543-56.
- Wu T, Liu Y, et al "Histone variant H2A.X deposition pattern serves as a functional epigenetic mark for distinguishing the developmental potentials of iPSCs." Cell Stem Cell. 2014;15:281-294.
- Woodcock CB, Yu D, Hajian T, Li J, Huang Y, Dai N, Corrêa IR Jr, Wu T, et al. "Human MettL3-MettL14 complex is a sequence-specific DNA adenine methyltransferase active on single-strand and unpaired DNA in vitro." Cell Discov.. 2019;5:63. Pubmed PMID: 31885874
- Zhang M, Yang S, Nelakanti R, Zhao W, Liu G, Li Z, Liu X, Wu T, et al. "Mammalian ALKBH1 serves as an N6-mA demethylase of unpairing DNA." Cell Res.. 2020;30:197-210. Pubmed PMID: 32051560
- Li X, Zhang Z, Luo X, Schrier J, Yang AD, Wu TP "The exploration of N6-deoxyadenosine methylation in mammalian genomes." Protein Cell. 2021 Oct;12:756-768. Pubmed PMID: 34405377
- Buganim Y, Markoulaki S, van Wietmarschen N, Hoke H, Wu T, et al "The developmental potential of iPSCs is greatly influenced by reprogramming factor selection." Cell Stem Cell. 2014;15:295-309.
- Dan J, Liu Y, Liu N, Chiourea M, Okuka M, Wu T, et al "Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing." Dev Cell. 2014;29:7-19.
- Zhang B*, Chen B*, Wu T*, Tan Y, et al "Estimating the quality of reprogrammed cells using ES cell differentiation expression patterns." PLoS One. 2011;6:e15336.
- Zhang B, Chen B, Wu T, Xuan Z, et al "Estimating developmental states of tumors and normal tissues using a linear time-ordered model." BMC Bioinformatics. 2011;12:53.
- Shi B*, Guo X*, Wu T*, et al "Genome-scale identification of Caenorhabditis elegans regulatory elements by tiling-array mapping of DNase I hypersensitive sites." BMC Genomics. 2009;10:92.
- He H, Wang J, Liu T, Liu XS, Li T, Wang Y, Qian Z, Zheng H, Zhu X, Wu T, et al "Mapping the C. elegans noncoding transcriptome with a whole-genome tiling microarray." Genome Res. 2007;17:1471-7.
- Wu T*, Wang J, Liu C, et al "NPInter: the noncoding RNAs and protein related biomacromolecules interaction database." Nucleic Acids Res. 2006;34:D150-2.
- Tan Y, Zhang B, Wu T, Skogerbø G, et al "Transcriptional inhibiton of Hoxd4 expression by miRNA-10a in human breast cancer cells." BMC Mol Biol. 2009;10:12.
- Scholar Cancer Prevention Research Institute of Texas (CPRIT)
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