1. Developing new technologies to study chromatin structure and function and gene regulation.
Less than 2% of the genome sequences are protein coding genes, while more than 98% of the human genome are non-coding sequence. Surprisingly, vast majority (~93%) of genetic variants that are associated with human traits and diseases lie in the non-coding genomic regions. When the human genome was first sequenced, these non-coding sequences were considered as non-essential and called as “junk DNA” or “dark matter”. However, accumulating evidence showed that these non-coding sequences can be epigenetically modified and bound by transcription factors to exert a critical role in regulating temporal-spatial gene expression program. Genetic and epigenetic alterations on these non-coding regulatory elements, such as promoter, enhancer, insulator, and silencer, often leads to human diseases. Yet, we still know little about the structure, function, regulation and biology of non-coding regulatory genome. We have a track record of developing new high-throughput genomics tools to further our understanding of chromatin biology. On this research direction, we are currently focused on the following topics: CRISPR-BioID; single-cell multi-omics profiling and perturbation; 3D genome analysis; and in vivo genome/epigenome engineering. These projects are funded by NHGRI Genome Innovator Awards, and the 4D Nucleome Consortium program by NIH Director's Office.
2. Gene regulation of skeletal muscle regeneration.
Muscle stem cell (MuSC), also known as satellite cell, is the major cell type that directly contributes to skeletal muscle development, growth and repair. In a broad spectrum of pathologic conditions, such as muscular dystrophy, aging, ischemia, and cachexia (devastating weight loss as well as muscle wasting associate with chronic conditions), accumulation of stem cell-intrinsic damages as well as the deleterious “niche” lead to a marked decline of muscle stem cell repair ability. MuSC transplantation offers great promise to treat muscular disorders, but its application has been hindered by a lack of understanding of the gene regulation mechanism that preserve stem cell long-term regenerative potency. Our group will strive to expand the understanding of the transcriptional and epigenetic control mechanism determining muscle stem cell quiescence, "alert", activation, self-renewal, and cell fate determination in health, disease, and aging. In the long run, we hope to translate the knowledge into innovative stem-cell based therapies to treat muscular disorders. These projects are support by NIH 4D Nucleome Consortium, American Federation for Aging Research (AFAR) and Glenn Foundation for Medical Research.
3. Gene regulation of rhabdomyosarcoma tumorigenesis.
Disruption of gene expression program causes diseases, including cancer. Rhabdomyosarcoma (RMS) is a life-threatening pediatric cancer often regarded as "myogenesis go awry" with imbalanced myogenic proliferation and differentiation program. Therefore, we hypothesize that the normal gene regulation mechanism that are needed for muscle repair are deregulated, by genetic or epigenetic alterations, in the RMS cells. We combine our expertise on myogenesis, high-throughput genomics analysis, CRISPR-BioID, and high-throughput CRISPR perturbation assays, in genetically engineered mouse model and human patient-derived RMS sphere culture, to generate data, analyze data, and formulate hypothesis from the data. We are closely collaborate with scientists and physicians at Duke and across the country to further our understanding of this deadly pediatric cancer. This research direction has been supported by V Scholar for Cancer Research, the Elsa U. Pardee Foundation, and Cancer Moonshot FusOnC2 Consortium.
Selected publications: (* equal contributation)
- Jung, I.*, Schmitt, A.*, Diao, Y.*, Yang, D., Chiang, Z., Chan, M., Tan, C., Barr, C.L., Li, B., Kuan, S., Kim, D., and Ren, B. (2019) A compendium of promoter-centered long-range chromatin interactions in 27 human tissues and cell types. Nature Genetics (in press)
- Chen, X., Wan, J., Yu, B., Diao, Y.#, and Zhang, W.# (2018) PIP5K1α promotes myogenic differentiation via AKT activation and calcium release. Stem Cell Res Ther. 9 (1), 33 (# co-corresponding author)
- Diao, Y., Fang, R., Li, B., Meng, Z., Yu, J., Qiu, Y., Lin, K.C., Huang, H., Liu, T., Marina, R.J., Jung, I., Shen, Y., Guan, K.L., and Ren, B. (2017). A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat Methods.
- An, Y.*, Wang, G.*, Diao, Y.*, Long, Y., Fu, X., Weng, M., Zhou, L., Sun, K., Cheung, T. H., Ip, N., Sun, H., Wang, H., and Wu, Z., (2017). A Molecular Switch Regulating the Cell Fate Choice Between Muscle Progenitor Cells and Brown Adipocytes. Dev Cell. 41, 382-391.
- Diao, Y., Li, B., Meng, Z., Jung, I., Lee, A.Y., Dixon, J., Maliskova, L., Guan, K.L., Shen, Y., and Ren, B. (2016). A new class of temporarily phenotypic enhancers identified by CRISPR/Cas9-mediated genetic screening. Genome Res. 26, 397-405.
- Diao, Y., Guo, X., Jiang, L., Wang, G., Zhang, C., Wan, J., Jin, Y., and Wu, Z. (2014). miR-203, a tumor suppressor frequently down-regulated by promoter hypermethylation in rhabdomyosarcoma. J Biol Chem 289, 529-539.
- Diao, Y., Guo, X., Li, Y., Sun, K., Lu, L., Jiang, L., Fu, X., Zhu, H., Sun, H., Wang, H., and Wu, Z. (2012). Pax3/7BP is a Pax7- and Pax3-binding protein that regulates the proliferation of muscle precursor cells by an epigenetic mechanism. Cell Stem Cell 11, 231-241.
- Diao, Y., Liu, W., Wong, C.C., Wang, X., Lee, K., Cheung, P.Y., Pan, L., Xu, T., Han, J., Yates, J.R., 3rd, Zhang, M., and Wu, Z. (2010). Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding. Proc Natl Acad Sci U S A 107, 20974-20979.
- Diao, Y., Wang, X., and Wu, Z. (2009). SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by inhibiting the leukemia inhibitory factor-induced JAK1/STAT1/STAT3 pathway. Mol Cell Biol 29, 5084-5093.