1. Developing new functional genomics and multi-omics tools to study chromatin structure and function .
Only less than 2% of the genome sequences are protein coding, 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 non-coding genome region. These non-coding sequences, previously considered as non-essential and called as “junk DNA” or “dark matter” when the human genome was first sequenced, are now recognized as important for controlling spatial-temporal gene expression. Indeed, it has been shown that the genetic and epigenetic changes of non-coding regulatory genome, such as promoter, enhancer, insulator, silencer or repressive elements, directly contribute to human diseases. Yet, we still know little about the structure, function, regulation and biology of non-coding regulatory genome. We will develop new high-throughput functional 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.
2. Transcriptional control of muscle stem cell and its supporting niche in tissue repair.
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. Our tissue regeneration and degeneration models includes: acute muscle injury (via intramuscular BaCl2 injection); physiological damage such as ischemia (via limb ischemia surgery); and aging(parabiosis).
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 cancer often regarded as "myogenesis go awry" with imbalanced myogenic proliferation and differentiation program. One of the aggressive subtype, Alveolar RMS (ARMS), is primarily driven by chromosomal translocations between the PAX3 (or PAX7) and FOXO1 loci. PAX3 and PAX7, the master transcription factors specifically expressed in muscle stem cell, are ectopically activated and highly expressed in ARMS cells. We hypothesize that upon chromosomal translocation, the "fused" cis-regulatory elements leads to the oncogenic activation of PAX fusion gene and results in RMS formation. To test this, we will combine epigenome and 3D-genome analysis, CRISPR-BioID, and high-throughput CRISPR perturbation, to delineate the gene regulatory network controlling the expression of PAX-FOXO1 fused oncogene. This research direction has been supported by V Scholar for Cancer Research, FusOnC2 Consortrium. Meanwhile, in addition to our interests on the fusion-positive ARMS, we are also interested in whether and how the deregulated tissue injury/regeneration signals will lead to uncontrolled proliferation of muscle stem cell, and eventually result in tumor formation.
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.