Research Directions
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1. Developing 'omics technologies to study chromatin structure and function in the context of 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.
Publications (updated in July 2023):
(# co-first author; * co-corresponding author)
Complete List of Published Work also available at: https://www.ncbi.nlm.nih.gov/myncbi/yarui.diao.1/bibliography/public/
and Google Scholar
(2018 - present, Diao lab@Duke Cell Biology)
1. Southerland KW, Xu Y, Peters DT, Wei X, Lin X, Xiang Y, Fei K, Olivere LA, Morowitz JM, Otto J, Dai Q, Kontos CD, Diao Y. Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells. bioRxiv. 2023 [cited 2023 Apr 9]. p. 2023.04.01.535211.
Available from: https://www.biorxiv.org/content/10.1101/2023.04.01.535211v1
2. Sun T, Xu Y, Xiang Y, Ou J, Soderblom EJ, Diao Y. Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells. Nat Genet. 2023 Jul 20;
Available from: http://dx.doi.org/10.1038/s41588-023-01452-5 PMCID: 6240941
- Accompanied Research Briefing in Nature Genetics: https://www.nature.com/articles/s41588-023-01453-4
3. Okafor AE, Lin X, Situ C, Wei X, Xiang Y, Wei X, Wu Z, Diao Y. Single-cell chromatin accessibility profiling reveals a self-renewing muscle satellite cell state. J Cell Biol. 2023 Aug 7;222(8).
Available from: http://dx.doi.org/10.1083/jcb.202211073 PMID: 37382627
- The processed scATAC-seq and scRNA-seq datasets reported in this study can be found from this interactive website: http://diaolab.rc.duke.edu/acute_injury/
4. Huang B, Zeng Z, Li H, Li Z, Chen X, Guo J, Zhang CC, Schreiber ME, Vonk AC, Xiang T, Patel T, Li Y, Parvez RK, Der B, Chen JH, Liu Z, Thornton ME, Grubbs BH, Diao Y, Dou Y, Gnedeva K, Lindström NO, Ying Q, Pastor-Soler NM, Fei T, Hallows KR, McMahon AP, Li Z. Modeling kidney development, disease, and plasticity with clonal expandable nephron progenitor cells and nephron organoids. bioRxiv. 2023 May 25;
Available from: http://dx.doi.org/10.1101/2023.05.25.542343 PMCID: PMC10245960
5. 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. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity. 2022 Dec 9;
Available from: http://dx.doi.org/10.1016/j.immuni.2022.11.013 PMID: 36521495
6. Bara AM, Chen L, Ma C, Underwood J, Moreci RS, Sumigray K, Sun T, Diao Y, Verzi M, Lechler T. Maf family transcription factors are required for nutrient uptake in the mouse neonatal gut. Development. 2022 Dec 1;149(23).
Available from: http://dx.doi.org/10.1242/dev.201251 PMID: 36504079
7. 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. Subtype-specific 3D genome alteration in acute myeloid leukaemia. Nature. 2022 Oct 26;
Available from: http://dx.doi.org/10.1038/s41586-022-05365-x PMID: 36289338
8. 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. The Hippo pathway mediates Semaphorin signaling. Sci Adv. 2022 May 27;8(21):eabl9806.
Available from: http://dx.doi.org/10.1126/sciadv.abl9806 PMCID: PMC9132450
9. Wang J, Broer T, Chavez T, Zhou CJ, Tran S, Xiang Y, Khodabukus A, Diao Y, Bursac N. Myoblast deactivation within engineered human skeletal muscle creates a transcriptionally heterogeneous population of quiescent satellite-like cells. Biomaterials. 2022 May;284:121508.
Available from: http://dx.doi.org/10.1016/j.biomaterials.2022.121508 PMCID: PMC9289780
10. Wei X, Xiang Y, Peters DT, Marius C, Sun T, Shan R, Ou J, Lin X, Yue F, Li W, Southerland KW, Diao Y. HiCAR is a robust and sensitive method to analyze open-chromatin-associated genome organization. Mol Cell. 2022 Mar 17;82(6):1225–1238.e6.
Available from: http://dx.doi.org/10.1016/j.molcel.2022.01.023 PMCID: PMC8934281
- Accompanied News and Views in Cell Genomics: https://www.sciencedirect.com/science/article/pii/S2666979X22000453
- Video abstract by Research Square: https://www.researchsquare.com/article/rs-2534301/v1
- HiCAR is recognized by Molecular Cell as "Best of 2022" technology breakthrough.
11. Tang YJ, Puviindran V, Xiang Y, Yahara Y, Zhang H, Nadesan P, Diao Y, Kirsch DG, Alman BA. Tumor-propagating side population cells are a dynamic subpopulation in undifferentiated pleomorphic sarcoma. JCI Insight. American Society for Clinical Investigation; 2021 Nov 22;6(22).
Available from: https://insight.jci.org/articles/view/148768 PMCID: PMC8663789
12. Li B, Chen PB, Diao Y. CRISPR-SE: a brute force search engine for CRISPR design. NAR Genom Bioinform. 2021 Mar;3(1):lqab013.
Available from: http://dx.doi.org/10.1093/nargab/lqab013 PMCID: PMC7902234
13. 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. BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis. Nat Genet. 2020 Dec;52(12):1384–1396.
Available from: http://dx.doi.org/10.1038/s41588-020-00729-3 PMID: 33139953
14. 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. Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair. Nat Cell Biol. 2020 Jan;22(1):49–59. Available from: http://dx.doi.org/10.1038/s41556-019-0437-8 PMCID: PMC6953622
15. Dall’Agnese A, Caputo L, Nicoletti C, di Iulio J, Schmitt A, Gatto S, Diao Y, Ye Z, Forcato M, Perera R, Bicciato S, Telenti A, Ren B, Puri PL. Transcription Factor-Directed Re-wiring of Chromatin Architecture for Somatic Cell Nuclear Reprogramming toward trans-Differentiation. Mol Cell. 2019 Nov 7;76(3):453–472.e8.
Available from: http://dx.doi.org/10.1016/j.molcel.2019.07.036 PMCID: PMC6842445
16. Wu S, Turner KM, Nguyen N, Raviram R, Erb M, Santini J, Luebeck J, Rajkumar U, Diao Y, Li B, Zhang W, Jameson N, Corces MR, Granja JM, Chen X, Coruh C, Abnousi A, Houston J, Ye Z, Hu R, Yu M, Kim H, Law JA, Verhaak RGW, Hu M, Furnari FB, Chang HY, Ren B, Bafna V, Mischel PS. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature. 2019 Nov;575(7784):699–703.
Available from: http://dx.doi.org/10.1038/s41586-019-1763-5 PMCID: PMC7094777
17. Jung I#, Schmitt A#, Diao Y#, Lee AJ, Liu T, Yang D, Tan C, Eom J, Chan M, Chee S, Chiang Z, Kim C, Masliah E, Barr CL, Li B, Kuan S, Kim D, Ren B. A compendium of promoter-centered long-range chromatin interactions in the human genome. Nat Genet. 2019 Oct;51(10):1442–1449.
Available from: http://dx.doi.org/10.1038/s41588-019-0494-8 PMCID: PMC6778519
18. 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. Neutrophils promote tumor resistance to radiation therapy. Proc Natl Acad Sci U S A . 2019 Sep 10;116(37):18584–18589.
Available from: http://dx.doi.org/10.1073/pnas.1901562116 PMCID: PMC6744874
19. Gao Y, Hisey E, Bradshaw TWA, Erata E, Brown WE, Courtland JL, Uezu A, Xiang Y, Diao Y, Soderling SH. Plug-and-Play Protein Modification Using Homology-Independent Universal Genome Engineering. Neuron. 2019 Aug 21;103(4):583–597.e8.
Available from: http://dx.doi.org/10.1016/j.neuron.2019.05.047 PMCID: PMC7200071
20. Chowdhry S, Zanca C, Rajkumar U, Koga T, Diao Y, Raviram R, Liu F, Turner K, Yang H, Brunk E, Bi J, Furnari F, Bafna V, Ren B, Mischel PS. NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature . 2019 May;569(7757):570–575.
Available from: http://dx.doi.org/10.1038/s41586-019-1150-2 PMCID: PMC7138021
21. Meng Z, Qiu Y, Lin KC, Kumar A, Placone JK, Fang C, Wang KC, Lu S, Pan M, Hong AW, Moroishi T, Luo M, Plouffe SW, Diao Y, Ye Z, Park HW, Wang X, Yu FX, Chien S, Wang CY, Ren B, Engler AJ, Guan KL. RAP2 mediates mechanoresponses of the Hippo pathway. Nature. 2018 Aug;560(7720):655–660.
Available from: http://dx.doi.org/10.1038/s41586-018-0444-0 PMCID: PMC6128698
22. Chen X, Wan J, Yu B, Diao Y*, Zhang W*. PIP5K1α promotes myogenic differentiation via AKT activation and calcium release. Stem Cell Res Ther. 2018 Feb 9;9(1):33.
Available from: http://dx.doi.org/10.1186/s13287-018-0770-z PMCID: PMC5806439
(Before 2018, prior to joining Duke Cell Biology)
23. Diao Y, Fang R, Li B, Meng Z, Yu J, Qiu Y, Lin KC, Huang H, Liu T, Marina RJ, Jung I, Shen Y, Guan KL, Ren B. A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat Methods. 2017 Jun;14(6):629–635.
Available from: http://dx.doi.org/10.1038/nmeth.4264 PMCID: PMC5490986
24. An Y#, Wang G#, Diao Y#, Long Y, Fu X, Weng M, Zhou L, Sun K, Cheung TH, Ip NY, Sun H, Wang H, Wu Z. A Molecular Switch Regulating Cell Fate Choice between Muscle Progenitor Cells and Brown Adipocytes. Dev Cell. 2017 May 22;41(4):382–391.e5.
Available from: http://dx.doi.org/10.1016/j.devcel.2017.04.012 PMID: 28535373
25. Zhu H, Xiao F, Wang G, Wei X, Jiang L, Chen Y, Zhu L, Wang H, Diao Y, Wang H, Ip NY, Cheung TH, Wu Z. STAT3 Regulates Self-Renewal of Adult Muscle Satellite Cells during Injury-Induced Muscle Regeneration. Cell Rep. 2016 Aug 23;16(8):2102–2115.
Available from: http://dx.doi.org/10.1016/j.celrep.2016.07.041 PMID: 27524611
26. Fan C, Wu Q, Ye X, Luo H, Yan D, Xiong Y, Zhu H, Diao Y, Zhang W, Wan J. Role of miR-211 in Neuronal Differentiation and Viability: Implications to Pathogenesis of Alzheimer’s Disease. Front Aging Neurosci . 2016 Jul 8;8:166.
Available from: http://dx.doi.org/10.3389/fnagi.2016.00166 PMCID: PMC4937029
27. Diao Y, Li B, Meng Z, Jung I, Lee AY, Dixon J, Maliskova L, Guan KL, Shen Y, Ren B. A new class of temporarily phenotypic enhancers identified by CRISPR/Cas9-mediated genetic screening. Genome Res . 2016 Mar;26(3):397–405.
Available from: http://dx.doi.org/10.1101/gr.197152.115 PMCID: PMC4772021
28. Ye X, Luo H, Chen Y, Wu Q, Xiong Y, Zhu J, Diao Y, Wu Z, Miao J, Wan J. MicroRNAs 99b-5p/100-5p Regulated by Endoplasmic Reticulum Stress are Involved in Abeta-Induced Pathologies. Front Aging Neurosci . 2015 Nov 18;7:210.
Available from: http://dx.doi.org/10.3389/fnagi.2015.00210 PMCID: PMC4649061
29. Wang Y, Zhao X, Ye X, Luo H, Zhao T, Diao Y, Zhang H, Lv M, Zhang W, Huang X, Wan J. Plasma microRNA-586 is a new biomarker for acute graft-versus-host disease. Ann Hematol . 2015 Sep;94(9):1505–1514.
Available from: http://dx.doi.org/10.1007/s00277-015-2414-z PMID: 26051902
30. Diao Y, Guo X, Jiang L, Wang G, Zhang C, Wan J, Jin Y, Wu Z. miR-203, a tumor suppressor frequently down-regulated by promoter hypermethylation in rhabdomyosarcoma. J Biol Chem. 2014 Jan 3;289(1):529–539.
Available from: http://dx.doi.org/10.1074/jbc.M113.494716 PMCID: PMC3879574
31. Dixon JR, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget JE, Lee AY, Ye Z, Kim A, Rajagopal N, Xie W, Diao Y, Liang J, Zhao H, Lobanenkov VV, Ecker JR, Thomson JA, Ren B. Chromatin architecture reorganization during stem cell differentiation. Nature . 2015 Feb 19;518(7539):331–336.
Available from: http://dx.doi.org/10.1038/nature14222 PMCID: PMC4515363
32. Luo H, Wu Q, Ye X, Xiong Y, Zhu J, Xu J, Diao Y, Zhang D, Wang M, Qiu J, Miao J, Zhang W, Wan J. Genome-wide analysis of miRNA signature in the APPswe/PS1ΔE9 mouse model of alzheimer’s disease. PLoS One . 2014 Aug 22;9(8):e101725.
Available from: http://dx.doi.org/10.1371/journal.pone.0101725 PMCID: PMC4141691
33. Diao Y, Guo X, Li Y, Sun K, Lu L, Jiang L, Fu X, Zhu H, Sun H, Wang H, Wu Z. 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 Aug 3;11(2):231–241.
Available from: http://dx.doi.org/10.1016/j.stem.2012.05.022 PMID: 22862948
34. Diao Y, Liu W, Wong CCL, Wang X, Lee K, Cheung PY, Pan L, Xu T, Han J, Yates JR 3rd, Zhang M, Wu Z. Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding. Proc Natl Acad Sci U S A . 2010 Dec 7;107(49):20974–20979.
Available from: http://dx.doi.org/10.1073/pnas.1007225107 PMCID: PMC3000308
35. 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 Sep;29(18):5084–5093.
Available from: http://dx.doi.org/10.1128/MCB.00267-09 PMCID: PMC2738280