Our goal is to understand the epigenetic mechanisms underlying craniofacial, neural and cancer development. We aim to identify the epigenetic components contributing to the unknown etiology of oral-facial clefting, autism, and to novel therapeutic targets for cancers. Histone methylation plays a major role in epigenetic regulation because of its dynamic nature subjected to the regulation by both intrinsic signals and environmental factors. We focus on the histone demethylase PHF8, whose enzymatic inactivation causes cleft lip/palate (CLP), and autism spectrum disorders (ASD). PHF8 is also over-expressed in prostate cancer cells and plays roles in the proliferation and migration of cancer cells. Thus, a second focus is to dissect the oncogenic mechanism by which PHF8 contributes to prostate cancer development. PHF8 acts as a transcriptional co-activator, by demethylating di-, mono-methylated lysine 9 of histone 3 (H3K9me2/me1) and mono-methylated lysine 20 of histone 4 (H4K20me1), both of which play important roles in regulating transcription, the cell cycle and genomic stability. ChIP-sequencing revealed that PHF8 targets many protein-coding genes as well as long intergenic non-coding (Linc) RNAs and microRNAs. The widespread nature of these genomic targets reders questions: what determine the transcriptional selectivity by PHF8? What are the immediate down-stream targets mediate PHF8 function in the context of embryonic development and cancer emergence. To tackle these questions, we employ biochemical techniques such as the TET-ON inducible gene over-expression/ knockdown system, cell culture-based analysis of signaling pathways, genome-wide ChIP-sequencing, RNA-sequencing, and conditional knockout mice. Our aims are as follows: 1). Establish the epigenetic mechanisms that underlie craniofacial and neural development. To this end, we are using PHF8 conditional knockout mice to dissect the developmental role of PHF8. Given that PHF8 uses oxygen as a co-factor for its demethylation activity, embryonic hypoxia (an epigenetic event that has been associated with CL/P and ASD) may directly impair its demethylation activity, thus, we are also investigating if PHF8 functions in the gene-environment (hypoxia) interaction that is associated with CL/P and ASD. We use cultured cells of oral-epithelial and mesenchymal origin, in vitro palate cultures, and hypoxia mouse models to investigate how hypoxia affects PHF8 function. 2). Identify the major development-associated signaling pathways whereby PHF8 contributes to specific transcriptional regulation. We are tackling if and how PHF8 interplays with the TGFβ, Notch and Wnt signaling pathways, and if it plays role in the EMT (epithelial to mesenchymal transition), one process known to underlie both palate fusion and cancer-cell metastasis. Moreover, we are profiling the histone methylation dynamics during EMT and aim to identify novel mechanism in the chromatin reprogramming. 3). Investigate the epigenetic mechanism in prostate cancer development. Histone demethylases, including LSD1, Plu1, PHF8, JmjD1A and JmjD2 family, play roles in the biology of prostate-cancer cells. We are particularly interested in how oncogenic histone demethylases, especially members of the PHF8 subfamily (e.g., PHF8, KIAA1718 and PHF2), participate in chromatin reprogramming in the prostate cancer cell differentiation and the development of prostate cancer stem cells.