The David Z. Rosensweig Genomics Research Center is applying genomic approaches to understand the causes and mechanisms of musculoskeletal and inflammatory conditions, including rheumatoid arthritis, osteoarthritis, tendon degeneration and associated muscle weakness, and bone loss in osteoporosis and orthopaedic implant loosening. The goal is to use this knowledge to develop personalized and effective new therapies that will restore mobility, enhance quality of life, and improve surgical outcomes for patients with rheumatologic and orthopedic disorders.
Established in 2013 with support from The Tow Foundation, the Genomics Center brings together a multidisciplinary team of scientists, clinicians, and computational biologists. The Genomics Center uses transcriptomics, epigenomics, and single-cell genomics to study disease genes and pathways, and is developing novel precision medicine therapeutic strategies for musculoskeletal conditions.
The goal of the computational group within the Genomics Center is to provide a full-stack consulting and analytical services for participating scientists and clinicians. We provide advice on experimental design, choice of appropriate technologies and analytical methods, perform data quality control and analysis, and create user-friendly reports and publication-ready data visualizations.
Rheumatoid Arthritis (RA)
- Mizoguchi F, Slowikowski K, Wei K, Marshall JL, Rao DA, Chang SK, Nguyen HN, Noss EH, Turner JD, Earp BE, Blazar PE, Wright J, Simmons BP, Donlin LT, Kalliolias GD, Goodman SM, Bykerk VP, Ivashkiv LB, Lederer JA, Hacohen N, Nigrovic PA, Filer A, Buckley CD, Raychaudhuri S, Brenner MB. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun. 2018 Feb 23;9(1):789.
- Stephenson W, Donlin LT, Butler A, Rozo C, Bracken B, Rashidfarrokhi A, Goodman SM, Ivashkiv LB, Bykerk VP, Orange DE, Darnell RB, Swerdlow HP, Satija R. Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation. Nat Commun. 2018 Feb 23;9(1):791.
- Orange DE, Agius P, DiCarlo EF, Robine N, Geiger H, Szymonifka J, McNamara M, Cummings R, Andersen KM, Mirza S, Figgie M, Ivashkiv L, Pernis AB, Jiang C, Frank M, Darnell R, Lingampali N, William R, Gravallese E, Bykerk VP, Goodman SM, Donlin LT; Accelerating Medicine Partnership: RA/SLE Network. Machine learning integration of rheumatoid arthritis synovial histology and RNAseq data identifies three disease subtypes. Arthritis Rheumatol. 2018 Feb 22.
- Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017 Feb ;542(7639):110-114.
- Loupasakis K, Kuo D, Sokhi UK, Sohn C, Syracuse B, et al. Tumor Necrosis Factor dynamically regulates the mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes. PLoS One. 2017;12(7):e0179762.
Systemic Lupus Erythematosus (SLE)
- Manni M, Gupta S, Ricker E, Chinenov Y, Park SH, Shi M, Pannellini T, Jessberger R, Ivashkiv LB, Pernis AB. Regulation of age-associated B cells by IRF5 in systemic autoimmunity. Nat Immunol. 2018 Feb 26.
- Yi W, Gupta S, Ricker E, Manni M, Jessberger R, et al. The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity. Nat Commun. 2017 Aug 15;8(1):254.
- Rozo C, Chinenov Y, Maharaj RK, Gupta S, Leuenberger L, et al. Targeting the RhoA ROCK pathway to reverse T-cell dysfunction in SLE. Ann Rheum Dis. 2017 Apr;76(4):740-747.
- Giannopoulou EG, Elemento O, Ivashkiv LB. Use of RNA sequencing to evaluate rheumatic disease patients. Arthritis Res Ther. 2015 Jul 1;17:167.
- Rogatsky I, Adelman K. Preparing the first responders: building the inflammatory transcriptome from the ground up. Mol Cell. 2014 Apr 24;54(2):245-54.
- Ah Kioon MD, Tripodo C, Fernandez D, Kirou KA, Spiera RF, Crow MK, Gordon JK, Barrat FJ. Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8. Science Translational Medicine. 2018;10(423).
- Laura T. Donlin*, Deepak A. Rao*, Kevin Wei, Kamil Slowikowski, Mandy J. McGeachy, Jason D. Turner, Nida Meednu, Fumitaka Mizoguchi, Maria Gutierrez-Arcelus, David J. Lieb, Joshua Keegan, Kaylin Muskat, Joshua Hillman, Cristina Rozo, Edd Ricker, Thomas M. Eisenhaure, Shuqiang Li, Edward P. Browne, Adam Chicoine, Danielle Sutherby, Akiko Noma, Accelerating Medicines Partnership: RA/SLE Network, Chad Nusbaum, Stephen Kelly, Alessandra B. Pernis, Lionel B. Ivashkiv, Susan M. Goodman, William H. Robinson, Paul J. Utz, James A. Lederer, Ellen M. Gravallese, Brendan F. Boyce, Nir Hacohen, Costantino Pitzalis, Peter K. Gregersen, Gary S. Firestein, Soumya Raychaudhuri, Larry W. Moreland, V. Michael Holers, Vivian P. Bykerk, Andrew Filer, David L. Boyle, Michael B. Brenner, Jennifer H. Anolik. High dimensional analyses of cells dissociated from cryopreserved synovial tissue. CSHL BioRxiv.
- Gupte R, Muse GW, Chinenov Y, Adelman K, and Rogatsky I. Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle. PNAS. 2013 Sep 3;110(36):14616-21.
- Sacta MA, Tharmalingam B, Coppo M, Rollins DA, Deochand DK, Benjamin B, Yu L, Zhang B, Hu X, Li R, Chinenov Y, Rogatsky I. Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages. Elife. 2018 Feb 9;7. pii: e34864.
- Rollins DA, Kharlyngdoh JB, Coppo M, Tharmalingam B, Mimouna S, et al. Glucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages. Nat Commun. 2017 Nov 23;8(1):1739.
- Park SH, Kang K, Giannopoulou E, Qiao Y, Kang K, et al. Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat Immunol. 2017 Oct;18(10):1104-1116.
- Kang K, Park SH, Chen J, Qiao Y, Giannopoulou E, et al. Interferon-γ Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF. Immunity. 2017 Aug 15;47(2):235-250.e4.
- Qiao Y, Kang K, Giannopoulou E, Fang C, Ivashkiv LB. IFN-γ Induces Histone 3 Lysine 27 Trimethylation in a Small Subset of Promoters to Stably Silence Gene Expression in Human Macrophages. Cell Rep. 2016 Sep 20;16(12):3121-3129.
- Coppo M, Chinenov Y, Sacta MA, Rogatsky I. The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis. Nat Commun. 2016 Jul 28;7:12254.
- Su X, Yu Y, Zhong Y, Giannopoulou EG, Hu X, et al. Interferon-γ regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat Immunol. 2015 Aug;16(8):838-849.
- Donlin LT, Jayatilleke A, Giannopoulou EG, Kalliolias GD, Ivashkiv LB. Modulation of TNF-induced macrophage polarization by synovial fibroblasts. J Immunol. 2014 Sep 1;193(5):2373-83.
- Qiao Y, Giannopoulou EG, Chan CH, Park SH, Gong S, et al. Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling. Immunity. 2013 Sep 19;39(3):454-69.
- Sokhi UK, Liber MP, Frye L, Park S, Kang K, Pannellini T, Zhao B, Norinsky R, Ivashkiv LB, Gong S. Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models. Nature Communications. 2018;9(1):658.
- Barrat FJ, Elkon KB, Fitzgerald KA. Importance of Nucleic Acid Recognition in Inflammation and Autoimmunity. Annual Review of Medicine. 2016;67:323-36.
- Murata K, Fang C, Terao C, Giannopoulou EG, Lee YJ, et al. Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis. Immunity. 2017 Jul 18;47(1):66-79.e5.
- Bae S, Lee MJ, Mun SH, Giannopoulou EG, Yong-Gonzalez V, et al. MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα. J Clin Invest. 2017 Jun 30;127(7):2555-2568.
- Binder N, Miller C, Yoshida M, Inoue K, Nakano S, et al. Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption. J Immunol. 2017 May 1;198(9):3436-3447.
- Park-Min KH. Epigenetic regulation of bone cells. Connect Tissue Res. 2017 Jan;58(1):76-89.
- Miller CH, Smith SM, Elguindy M, Zhang T, Xiang JZ, et al. RBP-J-Regulated miR-182 Promotes TNF-α-Induced Osteoclastogenesis. J Immunol. 2016 Jun 15;196(12):4977-86.
- Zheng HF, el. al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015;526(7571):112-7.
Orthopaedic Soft Tissue Research
The David Z. Rosensweig Genomics Research Center was founded with generous support provided by The Tow Foundation. This support has been leveraged to obtain additional funding from the National Institutes of Health, Department of Defense and various foundations and philanthropic organizations.
Additional Research Funding
- National Institutes of Health
- Department of Defense
- Lupus Research Alliance
- Arthritis National Research Foundation
- Rheumatology Research Foundation
- Feinstein Medical Foundation
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