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.
(# co-first author; * co-corresponding author)
PubMed and Google Scholar
(2018 - present, Diao lab@Duke Cell Biology)
1. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Wang X, He Q, Zhou C, Xu Y, Liu D, Fujiwara N, Kubota N, Click A, Henderson P, Vancil J, Marquez CA, Gunasekaran G, Schwartz ME, Tabrizian P, Sarpel U, Fiel MI, Diao Y, Sun B, Hoshida Y, Liang S, Zhong Z. Immunity. 2022 Dec 9; Available from: http://dx.doi.org/10.1016/j.immuni.2022.11.013 PMID: 36521495
2. Maf family transcription factors are required for nutrient uptake in the mouse neonatal gut. Bara AM, Chen L, Ma C, Underwood J, Moreci RS, Sumigray K, Sun T, Diao Y, Verzi M, Lechler T. Development. 2022 Dec 1;149(23). Available from: http://dx.doi.org/10.1242/dev.201251 PMID: 36504079
3. Subtype-specific 3D genome alteration in acute myeloid leukaemia. Xu J, Song F, Lyu H, Kobayashi M, Zhang B, Zhao Z, Hou Y, Wang X, Luan Y, Jia B, Stasiak L, Wong JHY, Wang Q, Jin Q, Jin Q, Fu Y, Yang H, Hardison RC, Dovat S, Platanias LC, Diao Y, Yang Y, Yamada T, Viny AD, Levine RL, Claxton D, Broach JR, Zheng H, Yue F. Nature. 2022 Oct 26; Available from: http://dx.doi.org/10.1038/s41586-022-05365-x PMID: 36289338
4. Identification of a self-renewing muscle satellite cell state by single-cell chromatin accessibility profiling
Okafor AE, Lin X, Situ C, Wei X, Wei X , Wu Z, Diao Y. bioRxiv. 2022 [cited 2022 Sep 28]. p. 2022.09.16.508339. Available from: https://www.biorxiv.org/content/10.1101/2022.09.16.508339v1
5. Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells Sun T, Xu Y, Xiang Y, Soderblom EJ, Diao Y. bioRxiv. 2022 [cited 2022 Sep 28]. p. 2022.09.08.507172. Available from: https://www.biorxiv.org/content/10.1101/2022.09.08.507172v1
6. The Hippo pathway mediates Semaphorin signaling.
Meng Z, Li FL, Fang C, Yeoman B, Qiu Y, Wang Y, Cai X, Lin KC, Yang D, Luo M, Fu V, Ma X, Diao Y, Giancotti FG, Ren B, Engler AJ, Guan KL.Sci Adv. 2022 May 27;8(21):eabl9806. doi: 10.1126/sciadv.abl9806. Epub 2022 May 25.PMID: 35613278
7. Myoblast deactivation within engineered human skeletal muscle creates a transcriptionally heterogeneous population of quiescent satellite-like cells.
Wang J, Broer T, Chavez T, Zhou CJ, Tran S, Xiang Y, Khodabukus A, Diao Y, Bursac N.Biomaterials. 2022 May;284:121508. doi: 10.1016/j.biomaterials.2022.121508. Epub 2022 Apr 7.PMID: 35421801
8. HiCAR is a robust and sensitive method to analyze open-chromatin-associated genome organization.
Wei X, Xiang Y, Peters DT, Marius C, Sun T, Shan R, Ou J, Lin X, Yue F, Li W, Southerland KW, Diao Y. Mol Cell. 2022 Mar 17;82(6):1225-1238.e6. doi: 10.1016/j.molcel.2022.01.023. Epub 2022 Feb 22.PMID: 35196517
Preview by Cell Genomics, 2022.
9. Tumor-propagating side population cells are a dynamic subpopulation in undifferentiated pleomorphic sarcoma.
Tang YJ, Puviindran V, Xiang Y, Yahara Y, Zhang H, Nadesan P, Diao Y, Kirsch DG, Alman BA. JCI Insight. 2021 Nov 22;6(22):e148768. doi: 10.1172/jci.insight.148768.PMID: 34618689
10. CRISPR-SE: a brute force search engine for CRISPR design.
Li B, Chen PB, Diao Y. NAR Genom Bioinform. 2021 Feb 23;3(1):lqab013. doi: 10.1093/nargab/lqab013. eCollection 2021 Mar.PMID: 33655210
11. BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis.
Fan H, Lu J, Guo Y, Li D, Zhang ZM, Tsai YH, Pi WC, Ahn JH, Gong W, Xiang Y, Allison DF, Geng H, He S, Diao Y, Chen WY, Strahl BD, Cai L, Song J, Wang GG. Nat Genet. 2020 Dec;52(12):1384-1396. doi: 10.1038/s41588-020-00729-3. Epub 2020 Nov 2.PMID: 33139953
12. Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair.
Yahara Y, Barrientos T, Tang YJ, Puviindran V, Nadesan P, Zhang H, Gibson JR, Gregory SG, Diao Y, Xiang Y, Qadri YJ, Souma T, Shinohara ML, Alman BA. Nat Cell Biol. 2020 Jan;22(1):49-59. doi: 10.1038/s41556-019-0437-8. Epub 2020 Jan 6.PMID: 31907410
13. Neutrophils promote tumor resistance to radiation therapy.
Wisdom AJ, Hong CS, Lin AJ, Xiang Y, Cooper DE, Zhang J, Xu ES, Kuo HC, Mowery YM, Carpenter DJ, Kadakia KT, Himes JE, Luo L, Ma Y, Williams N, Cardona DM, Haldar M, Diao Y, Markovina S, Schwarz JK, Kirsch DG. Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18584-18589. doi: 10.1073/pnas.1901562116. Epub 2019 Aug 28.PMID: 31462499
14. Plug-and-Play Protein Modification Using Homology-Independent Universal Genome Engineering.
Gao Y, Hisey E, Bradshaw TWA, Erata E, Brown WE, Courtland JL, Uezu A, Xiang Y, Diao Y, Soderling SH. Neuron. 2019 Aug 21;103(4):583-597.e8. doi: 10.1016/j.neuron.2019.05.047. Epub 2019 Jul 1.PMID: 31272828
15. PIP5K1α promotes myogenic differentiation via AKT activation and calcium release.
Chen X, Wan J, Yu B, Diao Y*, Zhang W.Stem Cell Res Ther. 2018 Feb 9;9(1):33. doi: 10.1186/s13287-018-0770-z.PMID: 29426367
(2013-2018, Yarui Diao's postdoc work@UC San Diego/Ludwig Institute for Cancer Reserach)
1 Dall’Agnese A, Caputo L, Nicoletti C, di Iulio J, Schmitt A, Gatto S, et al. Transcription Factor-Directed Re-wiring of Chromatin Architecture for Somatic Cell Nuclear Reprogramming toward trans-Differentiation. Mol Cell 2019;76:453–72.e8. https://doi.org/10.1016/j.molcel.2019.07.036.
2 Wu S, Turner KM, Nguyen N, Raviram R, Erb M, Santini J, et al. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature 2019;575:699–703. https://doi.org/10.1038/s41586-019-1763-5.
3 Jung I#, Schmitt A#, Diao Y#, Lee AJ, Liu T, Yang D, et al. A compendium of promoter-centered long-range chromatin interactions in the human genome. Nat Genet 2019;51:1442–9. https://doi.org/10.1038/s41588-019-0494-8.
4 Chowdhry S, Zanca C, Rajkumar U, Koga T, Diao Y, Raviram R, et al. NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature 2019;569:570–5. https://doi.org/10.1038/s41586-019-1150-2.
5 Meng Z, Qiu Y, Lin KC, Kumar A, Placone JK, Fang C, et al. RAP2 mediates mechanoresponses of the Hippo pathway. Nature 2018;560:655–60. https://doi.org/10.1038/s41586-018-0444-0.
6 Diao Y, Fang R, Li B, Meng Z, Yu J, Qiu Y, et al. A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat Methods 2017;14:629–35. https://doi.org/10.1038/nmeth.4264.
7 Diao Y, Li B, Meng Z, Jung I, Lee AY, Dixon J, et al. A new class of temporarily phenotypic enhancers identified by CRISPR/Cas9-mediated genetic screening. Genome Res 2016;26:397–405. https://doi.org/10.1101/gr.197152.115.
8 Dixon JR, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget JE, Lee AY, et al. Chromatin architecture reorganization during stem cell differentiation. Nature 2015;518:331–6. https://doi.org/10.1038/nature14222.
(2013-2018, Yarui Diao's PhD work@ The Hong Kong University of Science and Technology)
9 An Y#, Wang G#, Diao Y#, Long Y, Fu X, Weng M, et al. A Molecular Switch Regulating Cell Fate Choice between Muscle Progenitor Cells and Brown Adipocytes. Dev Cell 2017;41:382–91.e5. https://doi.org/10.1016/j.devcel.2017.04.012.
10 Zhu H, Xiao F, Wang G, Wei X, Jiang L, Chen Y, et al. STAT3 Regulates Self-Renewal of Adult Muscle Satellite Cells during Injury-Induced Muscle Regeneration. Cell Rep 2016;16:2102–15. https://doi.org/10.1016/j.celrep.2016.07.041.
11 Diao Y, Guo X, Jiang L, Wang G, Zhang C, Wan J, et al. miR-203, a tumor suppressor frequently down-regulated by promoter hypermethylation in rhabdomyosarcoma. J Biol Chem 2014;289:529–39. https://doi.org/10.1074/jbc.M113.494716.
12 Diao Y, Guo X, Li Y, Sun K, Lu L, Jiang L, et al. Pax3/7BP is a Pax7- and Pax3-binding protein that regulates the proliferation of muscle precursor cells by an epigenetic mechanism. Cell Stem Cell 2012;11:231–41. https://doi.org/10.1016/j.stem.2012.05.022.
13 Diao Y, Liu W, Wong CCL, Wang X, Lee K, Cheung P-Y, et al. Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding. Proc Natl Acad Sci U S A 2010;107:20974–9. https://doi.org/10.1073/pnas.1007225107.
14 Diao Y, Wang X, Wu Z. SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by inhibiting the leukemia inhibitory factor-induced JAK1/STAT1/STAT3 pathway. Mol Cell Biol 2009;29:5084–93. https://doi.org/10.1128/MCB.00267-09.