In the last year at graduate school, Tao began to tackle the question of how do cells commit to different cell fates with the same genomic DNA information? In 2010, Tao joined the newly established lab of Dr. Andrew Xiao at Yale to study epigenetics as a potential answer to this question. There, Tao utilized biochemistry and epigenetics approaches to complement his genomics expertise to tackle this problem. He applied these approaches to address the fundamental questions in the context of stem cell and Induced Pluripotent Stem Cell (iPSC) reprogramming. Identifying better biomarkers for assessing iPSC quality is an important goal for moving to clinical application. Instead of using transcriptional profiling or well-known histone modification markers, Tao discovered that an "epigenomic pattern mutation" of histone variants is essential for explaining the developmental variability of iPSCs. Tao discovered H2A.X, a histone variant of H2A that is usually involved in the DNA damage repair could mediate repression of extraembryonic lineage gene expression in embryonic stem cells (ESCs). He found that genomic deposition defects (called "epigenomic pattern mutation") frequently occur in the low-quality iPSC lines, whereas its deposition recapitulates the ESC's pattern in the high-quality iPSCs. The epigenomic pattern mutation of H2A.X leads to aberrant expression of extraembryonic lineage genes in low-quality iPSCs (which mimics the phenotype of H2A.X-knockout ESCs) and predisposes them to extraembryonic lineage differentiation in vitro and in vivo [6-8]. This work may pave the way for improved clinical application of iPSCs in regenerative medicine.
Following up on this discovery, Tao continued to dissect the mechanism of how H2A.X is targeted to specific genomic loci. To identify the unique property of DNA at H2A.X-nucleosome deposition sites, he developed a novel variation of ChIP-Seq, "SMRT-ChIP", which can simultaneously determine DNA modifications and genomic sequences of histone binding sites. This approach leverages native Chromatin Immunoprecipitation (N-ChIP) and the 3rd generation single-molecule real-time sequencing (SMRT) technology. By in depth analysis of H2A.X SMRT-ChIP data, he enjoyed a true "Eureka Moment". Tao discovered a novel mammalian DNA modification, DNA N6-methyladenine (N6-mdA). This is a form of DNA methylation that had not yet been detected in mammals [9, 10]. Tao also showed that ALKBH1 is major demethylase of N6-mdA, and the main function of N6-mdA is targeting and silencing evolutionarily younger LINE-1 retrotransposons in ESCs . The Identification of novel DNA modifications in mammalian genomes is a "holy-grail" question in the epigenetics field. Despite the extensive search by leading labs for over forty years, only 5-methylcytosine (5mC) and its derivatives were known as functional DNA modifications in mammals before 2016. Hence, Tao's work opened a new chapter in mammalian epigenetics and stem cell biology . Importantly, Tao was quickly appreciated the potential link between this DNA rare modification and malignant tumors. Thus, Tao initiated collaborations with leading cancer biology labs to show that while N6-mdA is rare in normal somatic cells, it is greatly enriched in high-grade glioblastoma patients' samples. He hypothesized that N6-mdA may be a mechanism by which cancer stem cells hijacks an early embryological mechanism for adapting to cancer niches and therapeutic resistance.
Dr. Wu will take advantage of the state-of-the-art resources of Baylor College of Medicine and the Texas Medical Center cancer community to continue to explore the fundamental epigenetic mechanisms underlying the anti-cancer therapeutic resistance. In addition to the classical pathways adapted by neoplastic cells to resist treatment, the co-opting of epigenetic regulatory processes is increasingly being recognized as an essential contributor to treatment resistance. By combining biochemical, epigenetic, and bioinformatics approaches, Dr. Wu will define new vulnerabilities that can be targeted to overcome therapeutic resistance in cancer treatment.