Email

tw9@bcm.edu

Positions

Assistant Professor

Molecular and Human Genetics
Baylor College of Medicine
Houston, TX, US

Education

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

Professional Interests

• Deciphering the Driver Epigenetic Mutations in Cancer
• Understanding the Dynamics of Epigenetic Regulation
• Overcoming the Cancer Treatment Resistance

Professional Statement

The core question our lab wants to answer is how the epigenetic factors dynamically regulate the cell fate decision and the response to external stimulation. Our final goal is to apply the fundamental knowledge for curing human diseases, such as cancer. 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, the cancer treatment resistance is still the 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. Recently, using 2nd generation high-throughput sequencing, about 50% of human cancers were found to harbor mutations in the epigenetic regulatory enzymes which are involved in chromatin organization. Meanwhile, the 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, a DNA methylation that had never been detected in mammals before) with SMRT-ChIP (3rd generation single-molecule real-time sequencing with native ChIP samples) in mouse ES cells. We also identified ALKBH1 as the major demethylase of DNA 6mA. Very recently, we pinpointed that 6mA level is ultra-high in glioblastoma stem cells and high-grade glioblastoma (GBM) patient’s samples. In contrast, the 6mA’s abundance is much lower in the differentiated 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, I hypothesize that DNA 6mA might be a driver epigenetic mutation and its regulators could constitute an essential pathway which manipulates cancer treatment resistance. The DNA 6mA’s readers, writers, or erasers, could be defined as new cancer dependencies which could be targeted to bypass the resistance and enhance the cancer 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 optimized CRISPR/Cas9 screening approaches, we will explore new cancer dependencies with the novel DNA or histone modifications in different model systems.

Selected Publications

• Wu TP, Wang T, et al "DNA methylation on N(6)-adenine in mammalian embryonic stem cells.." Nature. 2016 532 : 329-33.
• Xie Q*, Wu TP*, Gimple RC*, et al "N(6)-methyladenine DNA Modification in Glioblastoma." Cell. 2018 October 30; : Pubmed PMID: 30392959
• 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.

Funding

Scholar

Cancer Prevention Research Institute of Texas (CPRIT)