1. Decoding the regulatory role of non-coding genome sequence.
More than 98% of the human genome are non-coding sequence, and vast majority (~93%) of human disease and traits associated risk variants lie in these non-coding regions. These non-coding regions, that were previously considered as non-essential and called as “junk DNA” or “dark matter” in the genome, are now recognized as important for controlling spatiotemporal gene expression. A growing body of evidence indicates in many cases that the genetic and epigenetic variants underlying the non-coding regulatory sequences, such as enhancer, insulator, and repressive elements, contribute to human diseases. Yet, we know little about the consequences and mechanisms of how cis-regulatory element and disease-associated non-coding variations regulate development, tissue regeneration, degenerative disorders, and cancer. Our lab will develop and apply innovative high-throughput functional genomics and genome editing tools that allow us to investigate how the “junk DNA” interplay with transcription factors and epigenetic mechanism to control gene regulation.
2. Dissecting the transcriptional regulatory network that controls muscle stem cell regeneration capacity.
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, and cachexia (devastating weight loss as well as muscle wasting associate with chronic conditions, such as cancer, diabetes, HIV, and multiple sclerosis), the deleterious stem-cell “niche” and accumulation of cell-intrinsic damages 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 regulatory network, which involves epigenetic, trans- and cis-acting factors and controls muscle stem cell quiescence, 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.
3. The genetic and epigenetic basis of rhabdomyosarcoma development.
Disruption of gene expression program causes diseases, including cancer. Rhabdomyosarcoma (RMS) is a life-threatening pediatric sarcoma, shows imbalanced regulation of proliferation and myogenic differentiation. One of the aggressive subtype, Alveolar RMS (ARMS), is primarily driven by chromosomal translocations between the PAX3 (or PAX7) and FOXO1 loci. Although the genetic lesions resulting in ARMS has been well documented for about 30 years, the targeted therapies for ARMS are still lacking, mainly due to a lack of in-depth understanding of the molecular machinery that drives the ectopic expression of PAX-FOXO1 oncogene. We hypothesize that upon chromosomal translocation, the "fused" cis-regulatory elements activate the promoter of PAX fusion gene, which in turn leads to RMS formation. To test this, we will combine NGS-based epigenome and 3D-genome analysis, high-throughput CRISPR/Cas9-based approaches, as well as new animal models, to identify the "oncogenic enhancers" and uncover the gene regulation network that control PAX-FOXO1 oncogene expression and RMS progression.
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.