PMID- 34230488 OWN - NLM STAT- In-Data-Review LR - 20210707 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 12 IP - 1 DP - 2021 Jul 6 TI - Joint disease-specificity at the regulatory base-pair level. PG - 4161 LID - 10.1038/s41467-021-24345-9 [doi] AB - Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations. FAU - Muthuirulan, Pushpanathan AU - Muthuirulan P AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. FAU - Zhao, Dewei AU - Zhao D AD - Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China. FAU - Young, Mariel AU - Young M AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. FAU - Richard, Daniel AU - Richard D AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. FAU - Liu, Zun AU - Liu Z AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. FAU - Emami, Alireza AU - Emami A AD - Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Portilla, Gabriela AU - Portilla G AD - Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Hosseinzadeh, Shayan AU - Hosseinzadeh S AUID- ORCID: 0000-0002-5326-6852 AD - Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Cao, Jiaxue AU - Cao J AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. AD - Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China. FAU - Maridas, David AU - Maridas D AD - Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA. FAU - Sedlak, Mary AU - Sedlak M AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. FAU - Menghini, Danilo AU - Menghini D AD - Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Cheng, Liangliang AU - Cheng L AD - Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China. FAU - Li, Lu AU - Li L AD - Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China. FAU - Ding, Xinjia AU - Ding X AD - Department of Surgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China. FAU - Ding, Yan AU - Ding Y AUID- ORCID: 0000-0002-7708-4391 AD - Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Rosen, Vicki AU - Rosen V AUID- ORCID: 0000-0002-4029-1055 AD - Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA. FAU - Kiapour, Ata M AU - Kiapour AM AUID- ORCID: 0000-0001-7742-5769 AD - Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. ata.kiapour@childrens.harvard.edu. FAU - Capellini, Terence D AU - Capellini TD AUID- ORCID: 0000-0003-3842-8478 AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. tcapellini@fas.harvard.edu. AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. tcapellini@fas.harvard.edu. LA - eng GR - R01AR065462/U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/ GR - 1R01AR070139/U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/ GR - BCS1518596/National Science Foundation (NSF)/ PT - Journal Article DEP - 20210706 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 SB - IM EDAT- 2021/07/08 06:00 MHDA- 2021/07/08 06:00 CRDT- 2021/07/07 06:24 PHST- 2020/12/17 00:00 [received] PHST- 2021/06/16 00:00 [accepted] PHST- 2021/07/07 06:24 [entrez] PHST- 2021/07/08 06:00 [pubmed] PHST- 2021/07/08 06:00 [medline] AID - 10.1038/s41467-021-24345-9 [pii] AID - 10.1038/s41467-021-24345-9 [doi] PST - epublish SO - Nat Commun. 2021 Jul 6;12(1):4161. doi: 10.1038/s41467-021-24345-9. PMID- 34138751 OWN - NLM STAT- In-Process LR - 20210711 IS - 1945-4589 (Electronic) IS - 1945-4589 (Linking) VI - 13 IP - 12 DP - 2021 Jun 16 TI - Shifting epigenetic contexts influence regulatory variation and disease risk. PG - 15699-15749 LID - 10.18632/aging.203194 [doi] AB - Epigenetic shifts are a hallmark of aging that impact transcriptional networks at regulatory level. These shifts may modify the effects of genetic regulatory variants during aging and contribute to disease pathomechanism. However, these shifts occur on the backdrop of epigenetic changes experienced throughout an individual's development into adulthood; thus, the phenotypic, and ultimately fitness, effects of regulatory variants subject to developmental- versus aging-related epigenetic shifts may differ considerably. Natural selection therefore may act differently on variants depending on their changing epigenetic context, which we propose as a novel lens through which to consider regulatory sequence evolution and phenotypic effects. Here, we define genomic regions subjected to altered chromatin accessibility as tissues transition from their fetal to adult forms, and subsequently from early to late adulthood. Based on these epigenomic datasets, we examine patterns of evolutionary constraint and potential functional impacts of sequence variation (e.g., genetic disease risk associations). We find that while the signals observed with developmental epigenetic changes are consistent with stronger fitness consequences (i.e., negative selection pressures), they tend to have weaker effects on genetic risk associations for aging-related diseases. Conversely, we see stronger effects of variants with increased local accessibility in adult tissues, strongest in young adult when compared to old. We propose a model for how epigenetic status of a region may influence the effects of evolutionary relevant sequence variation, and suggest that such a perspective on gene regulatory networks may elucidate our understanding of aging biology. FAU - Richard, Daniel AU - Richard D AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA. FAU - Capellini, Terence D AU - Capellini TD AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA. AD - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210616 TA - Aging (Albany NY) JT - Aging JID - 101508617 SB - IM PMC - PMC8266365 OTO - NOTNLM OT - *GWAS OT - *aging OT - *development OT - *disease OT - *evolution COIS- CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest. EDAT- 2021/06/18 06:00 MHDA- 2021/06/18 06:00 CRDT- 2021/06/17 17:20 PHST- 2021/04/08 00:00 [received] PHST- 2021/06/01 00:00 [accepted] PHST- 2021/06/18 06:00 [pubmed] PHST- 2021/06/18 06:00 [medline] PHST- 2021/06/17 17:20 [entrez] AID - 203194 [pii] AID - 10.18632/aging.203194 [doi] PST - ppublish SO - Aging (Albany NY). 2021 Jun 16;13(12):15699-15749. doi: 10.18632/aging.203194. Epub 2021 Jun 16. PMID- 33973737 OWN - NLM STAT- Publisher LR - 20210511 IS - 2326-5205 (Electronic) IS - 2326-5191 (Linking) DP - 2021 May 11 TI - Subchondral bone length in knee osteoarthritis: A deep learning derived imaging measure and its association with radiographic and clinical outcomes. LID - 10.1002/art.41808 [doi] AB - OBJECTIVE: Develop a bone shape measure that reflects the extent of cartilage loss and bone flattening in knee osteoarthritis (OA) and test it against estimates of disease severity. METHODS: A fast region-based convolutional neural network was trained to crop the knee joints in sagittal dual-echo steady state MRI sequences obtained from the Osteoarthritis Initiative (OAI). Publicly available annotations of the cartilage and menisci were used as references to annotate the tibia and the femur in 61 knees. Another deep neural network (U-Net) was developed to learn these annotations. Model predictions were compared with radiologist-driven annotations on an independent test set (27 knees). The U-Net was applied to automatically extract the knee joint structures on the larger OAI dataset (9,434 knees). We defined subchondral bone length (SBL), a novel shape measure characterizing the extent of overlying cartilage and bone flattening, and examined its relationship with radiographic joint space narrowing (JSN), concurrent WOMAC pain and disability as well as subsequent partial or total knee replacement (KR). Odds ratios for each outcome were estimated using relative changes in SBL on the OAI dataset into quartiles. RESULT: Mean SBL values for knees with JSN were consistently different from knees without JSN. Greater changes of SBL from baseline were associated with greater pain and disability. For knees with medial or lateral JSN, the odds ratios between lowest and highest quartiles corresponding to SBL changes for future KR were 5.68 (95% CI:[3.90,8.27]) and 7.19 (95% CI:[3.71,13.95]), respectively. CONCLUSION: SBL quantified OA status based on JSN severity. It has promise as an imaging marker in predicting clinical and structural OA outcomes. CI - This article is protected by copyright. All rights reserved. FAU - Chang, Gary H AU - Chang GH AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Park, Lisa K AU - Park LK AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Le, Nina A AU - Le NA AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Jhun, Ray S AU - Jhun RS AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Surendran, Tejus AU - Surendran T AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Lai, Joseph AU - Lai J AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Seo, Hojoon AU - Seo H AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Promchotichai, Nuwapa AU - Promchotichai N AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Yoon, Grace AU - Yoon G AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Scalera, Jonathan AU - Scalera J AD - Department of Radiology, Boston University School of Medicine, Boston, MA, USA, 02118. FAU - Capellini, Terence D AU - Capellini TD AUID- ORCID: 0000-0003-3842-8478 AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA, 02138. AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA, 02142. FAU - Felson, David T AU - Felson DT AUID- ORCID: 0000-0002-2668-2447 AD - Section of Rheumatology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA - 02118; Centre for Epidemiology, University of Manchester and the NIHR Manchester BRC, Manchester University, NHS Trust, Manchester, UK. FAU - Kolachalama, Vijaya B AU - Kolachalama VB AUID- ORCID: 0000-0002-5312-8644 AD - Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 02118. AD - Department of Computer Science, Faculty of Computing & Data Sciences, Boston University, Boston, MA, USA, 02215. LA - eng PT - Journal Article DEP - 20210511 PL - United States TA - Arthritis Rheumatol JT - Arthritis & rheumatology (Hoboken, N.J.) JID - 101623795 SB - AIM SB - IM OTO - NOTNLM OT - Deep Learning OT - Joint Space Narrowing OT - Knee Osteoarthritis OT - Knee Replacement OT - Magnetic Resonance Imaging EDAT- 2021/05/12 06:00 MHDA- 2021/05/12 06:00 CRDT- 2021/05/11 09:39 PHST- 2021/05/11 09:39 [entrez] PHST- 2021/05/12 06:00 [pubmed] PHST- 2021/05/12 06:00 [medline] AID - 10.1002/art.41808 [doi] PST - aheadofprint SO - Arthritis Rheumatol. 2021 May 11. doi: 10.1002/art.41808. PMID- 33937724 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210604 IS - 2589-0042 (Electronic) IS - 2589-0042 (Linking) VI - 24 IP - 5 DP - 2021 May 21 TI - Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses. PG - 102477 LID - 10.1016/j.isci.2021.102477 [doi] LID - 102477 AB - Type I interferons (IFNs) are our first line of defense against virus infection. Recent studies have suggested the ability of SARS-CoV-2 proteins to inhibit IFN responses. Emerging data also suggest that timing and extent of IFN production is associated with manifestation of COVID-19 severity. In spite of progress in understanding how SARS-CoV-2 activates antiviral responses, mechanistic studies into wild-type SARS-CoV-2-mediated induction and inhibition of human type I IFN responses are scarce. Here we demonstrate that SARS-CoV-2 infection induces a type I IFN response in vitro and in moderate cases of COVID-19. In vitro stimulation of type I IFN expression and signaling in human airway epithelial cells is associated with activation of canonical transcriptions factors, and SARS-CoV-2 is unable to inhibit exogenous induction of these responses. Furthermore, we show that physiological levels of IFNα detected in patients with moderate COVID-19 is sufficient to suppress SARS-CoV-2 replication in human airway cells. CI - © 2021 The Author(s). FAU - Banerjee, Arinjay AU - Banerjee A AD - Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - El-Sayes, Nader AU - El-Sayes N AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Budylowski, Patrick AU - Budylowski P AD - Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada. FAU - Jacob, Rajesh Abraham AU - Jacob RA AD - Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Richard, Daniel AU - Richard D AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA. FAU - Maan, Hassaan AU - Maan H AD - Vector Institute for Artificial Intelligence, Toronto, ON M5G 1M1, Canada. AD - Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 2C4, Canada. FAU - Aguiar, Jennifer A AU - Aguiar JA AD - Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada. FAU - Demian, Wael L AU - Demian WL AD - Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Baid, Kaushal AU - Baid K AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - D'Agostino, Michael R AU - D'Agostino MR AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Ang, Jann Catherine AU - Ang JC AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Murdza, Tetyana AU - Murdza T AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Tremblay, Benjamin J-M AU - Tremblay BJ AD - Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada. FAU - Afkhami, Sam AU - Afkhami S AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Karimzadeh, Mehran AU - Karimzadeh M AD - Vector Institute for Artificial Intelligence, Toronto, ON M5G 1M1, Canada. FAU - Irving, Aaron T AU - Irving AT AD - Zhejiang University - University of Edinburgh Institute, Haining, Zhejiang 314400, China. AD - Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310027, China. FAU - Yip, Lily AU - Yip L AD - Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada. FAU - Ostrowski, Mario AU - Ostrowski M AD - Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada. AD - Keenan Research Centre for Biomedical Science of St. Michael's Hospital, UnityHealth, Toronto, ON M5B 1W8, Canada. FAU - Hirota, Jeremy A AU - Hirota JA AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. AD - Division of Respiratory Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada. FAU - Kozak, Robert AU - Kozak R AD - Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada. AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada. FAU - Capellini, Terence D AU - Capellini TD AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA. FAU - Miller, Matthew S AU - Miller MS AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Wang, Bo AU - Wang B AD - Vector Institute for Artificial Intelligence, Toronto, ON M5G 1M1, Canada. AD - Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 2C4, Canada. AD - Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada. AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada. FAU - Mubareka, Samira AU - Mubareka S AD - Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada. AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada. FAU - McGeer, Allison J AU - McGeer AJ AD - Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. AD - Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5S 1A1, Canada. FAU - McArthur, Andrew G AU - McArthur AG AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. FAU - Doxey, Andrew C AU - Doxey AC AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada. FAU - Mossman, Karen AU - Mossman K AD - Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. AD - Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada. AD - McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. LA - eng PT - Journal Article DEP - 20210426 TA - iScience JT - iScience JID - 101724038 PMC - PMC8074517 OTO - NOTNLM OT - Immunology OT - Virology COIS- The authors declare no competing interests. EDAT- 2021/05/04 06:00 MHDA- 2021/05/04 06:01 CRDT- 2021/05/03 06:27 PHST- 2020/10/30 00:00 [received] PHST- 2021/02/26 00:00 [revised] PHST- 2021/04/23 00:00 [accepted] PHST- 2021/05/04 06:00 [pubmed] PHST- 2021/05/04 06:01 [medline] PHST- 2021/05/03 06:27 [entrez] AID - S2589-0042(21)00445-4 [pii] AID - 102477 [pii] AID - 10.1016/j.isci.2021.102477 [doi] PST - ppublish SO - iScience. 2021 May 21;24(5):102477. doi: 10.1016/j.isci.2021.102477. Epub 2021 Apr 26. PMID- 33559841 OWN - NLM STAT- In-Data-Review LR - 20210402 IS - 1544-2241 (Electronic) IS - 1544-1873 (Linking) VI - 19 IP - 2 DP - 2021 Apr TI - Single Cell Omics for Musculoskeletal Research. PG - 131-140 LID - 10.1007/s11914-021-00662-2 [doi] AB - PURPOSE OF REVIEW: The ability to analyze the molecular events occurring within individual cells as opposed to populations of cells is revolutionizing our understanding of musculoskeletal tissue development and disease. Single cell studies have the great potential of identifying cellular subpopulations that work in a synchronized fashion to regenerate and repair damaged tissues during normal homeostasis. In addition, such studies can elucidate how these processes break down in disease as well as identify cellular subpopulations that drive the disease. This review highlights three emerging technologies: single cell RNA sequencing (scRNA-seq), Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq), and Cytometry by Time-Of-Flight (CyTOF) mass cytometry. RECENT FINDINGS: Technological and bioinformatic tools to analyze the transcriptome, epigenome, and proteome at the individual cell level have advanced rapidly making data collection relatively easy; however, understanding how to access and interpret the data remains a challenge for many scientists. It is, therefore, of paramount significance to educate the musculoskeletal community on how single cell technologies can be used to answer research questions and advance translation. This article summarizes talks given during a workshop on "Single Cell Omics" at the 2020 annual meeting of the Orthopedic Research Society. Studies that applied scRNA-seq, ATAC-seq, and CyTOF mass cytometry to cartilage development and osteoarthritis are reviewed. This body of work shows how these cutting-edge tools can advance our understanding of the cellular heterogeneity and trajectories of lineage specification during development and disease. FAU - Rai, Muhammad Farooq AU - Rai MF AD - Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA. FAU - Wu, Chia-Lung AU - Wu CL AD - Department of Orthopaedic Surgery, Washington University and Shriners Hospitals for Children, St. Louis, MO, USA. FAU - Capellini, Terence D AU - Capellini TD AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. FAU - Guilak, Farshid AU - Guilak F AD - Department of Orthopaedic Surgery, Washington University and Shriners Hospitals for Children, St. Louis, MO, USA. FAU - Dicks, Amanda R AU - Dicks AR AD - Department of Orthopaedic Surgery, Washington University and Shriners Hospitals for Children, St. Louis, MO, USA. FAU - Muthuirulan, Pushpanathan AU - Muthuirulan P AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. FAU - Grandi, Fiorella AU - Grandi F AD - Department of Orthopedic Surgery, Stanford University, Stanford, CA, USA. FAU - Bhutani, Nidhi AU - Bhutani N AD - Department of Orthopedic Surgery, Stanford University, Stanford, CA, USA. FAU - Westendorf, Jennifer J AU - Westendorf JJ AUID- ORCID: 0000-0002-4464-6108 AD - Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA. westendorf.jennifer@mayo.edu. LA - eng GR - AR075899/AR/NIAMS NIH HHS/United States GR - AR070864/AR/NIAMS NIH HHS/United States GR - AR070865/AR/NIAMS NIH HHS/United States GR - AR070139/AR/NIAMS NIH HHS/United States GR - AG15768/AG/NIA NIH HHS/United States GR - AR075899/AR/NIAMS NIH HHS/United States GR - AR070864/AR/NIAMS NIH HHS/United States GR - AR070865/AR/NIAMS NIH HHS/United States GR - AR070139/AR/NIAMS NIH HHS/United States GR - AG15768/AG/NIA NIH HHS/United States PT - Journal Article PT - Review DEP - 20210209 PL - United States TA - Curr Osteoporos Rep JT - Current osteoporosis reports JID - 101176492 SB - IM OTO - NOTNLM OT - ATAC-seq OT - Cartilage OT - CyTOF OT - Osteoarthritis OT - Single cell RNA-seq EDAT- 2021/02/10 06:00 MHDA- 2021/02/10 06:00 CRDT- 2021/02/09 08:48 PHST- 2021/01/19 00:00 [accepted] PHST- 2021/02/10 06:00 [pubmed] PHST- 2021/02/10 06:00 [medline] PHST- 2021/02/09 08:48 [entrez] AID - 10.1007/s11914-021-00662-2 [pii] AID - 10.1007/s11914-021-00662-2 [doi] PST - ppublish SO - Curr Osteoporos Rep. 2021 Apr;19(2):131-140. doi: 10.1007/s11914-021-00662-2. Epub 2021 Feb 9. PMID- 33448926 OWN - NLM STAT- In-Data-Review LR - 20210121 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 10 DP - 2021 Jan 15 TI - Bi-fated tendon-to-bone attachment cells are regulated by shared enhancers and KLF transcription factors. LID - 10.7554/eLife.55361 [doi] LID - e55361 AB - The mechanical challenge of attaching elastic tendons to stiff bones is solved by the formation of a unique transitional tissue. Here, we show that murine tendon-to-bone attachment cells are bi-fated, activating a mixture of chondrocyte and tenocyte transcriptomes, under regulation of shared regulatory elements and Krüppel-like factors (KLFs) transcription factors. High-throughput bulk and single-cell RNA sequencing of humeral attachment cells revealed expression of hundreds of chondrogenic and tenogenic genes, which was validated by in situ hybridization and single-molecule ISH. ATAC sequencing showed that attachment cells share accessible intergenic chromatin areas with either tenocytes or chondrocytes. Epigenomic analysis revealed enhancer signatures for most of these regions. Transgenic mouse enhancer reporter assays verified the shared activity of some of these enhancers. Finally, integrative chromatin and motif analyses and transcriptomic data implicated KLFs as regulators of attachment cells. Indeed, blocking expression of both Klf2 and Klf4 in developing limb mesenchyme impaired their differentiation. CI - © 2021, Kult et al. FAU - Kult, Shiri AU - Kult S AUID- ORCID: 0000-0001-8216-2908 AD - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. FAU - Olender, Tsviya AU - Olender T AD - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. FAU - Osterwalder, Marco AU - Osterwalder M AUID- ORCID: 0000-0002-1969-2313 AD - Environmental Genomics and Systems Biology Division, Lawrence Berkeley National, Berkeley, United States. AD - Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. FAU - Markman, Svetalana AU - Markman S AD - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. FAU - Leshkowitz, Dena AU - Leshkowitz D AD - Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. FAU - Krief, Sharon AU - Krief S AD - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. FAU - Blecher-Gonen, Ronnie AU - Blecher-Gonen R AD - Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. FAU - Ben-Moshe, Shani AU - Ben-Moshe S AD - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. FAU - Farack, Lydia AU - Farack L AUID- ORCID: 0000-0001-9597-5078 AD - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. FAU - Keren-Shaul, Hadas AU - Keren-Shaul H AD - Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. FAU - Salame, Tomer-Meir AU - Salame TM AD - Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. FAU - Capellini, Terence D AU - Capellini TD AUID- ORCID: 0000-0003-3842-8478 AD - Department of Human Evolutionary Biology, Harvard University, Department of Human Evolutionary Biology, United States; Broad Institute of Harvard and MIT, Cambridge, United States. FAU - Itzkovitz, Shalev AU - Itzkovitz S AUID- ORCID: 0000-0003-0685-2522 AD - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. FAU - Amit, Ido AU - Amit I AD - Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. FAU - Visel, Axel AU - Visel A AUID- ORCID: 0000-0002-4130-7784 AD - Environmental Genomics and Systems Biology Division, Lawrence Berkeley National, Berkeley, United States. AD - U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, United States. AD - School of Natural Sciences, University of California, Merced, Merced, United States. FAU - Zelzer, Elazar AU - Zelzer E AUID- ORCID: 0000-0002-1584-6602 AD - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. LA - eng SI - GEO/GSE144306 SI - GEO/GSE160090 GR - R01 HG003988/HG/NHGRI NIH HHS/United States GR - R01 AR055580/AR/NIAMS NIH HHS/United States GR - R01HG003988/NH/NIH HHS/United States GR - DEAC02-05CH11231/University of California/ GR - grant No. 713533/Minerva Foundation/ GR - grant No. 345/16/Israel Science Foundation/ GR - PCEFP3_186993/SNSF_/Swiss National Science Foundation/Switzerland GR - R01 AR055580/NH/NIH HHS/United States PT - Journal Article DEP - 20210115 TA - Elife JT - eLife JID - 101579614 SB - IM PMC - PMC7810463 OTO - NOTNLM OT - cartilage OT - developmental biology OT - enthesis OT - mouse OT - musculoskeletal system OT - tendon COIS- SK, TO, MO, SM, DL, SK, RB, SB, LF, HK, TS, TC, SI, IA, AV, EZ No competing interests declared EDAT- 2021/01/16 06:00 MHDA- 2021/01/16 06:00 CRDT- 2021/01/15 12:10 PHST- 2020/01/21 00:00 [received] PHST- 2020/11/30 00:00 [accepted] PHST- 2021/01/15 12:10 [entrez] PHST- 2021/01/16 06:00 [pubmed] PHST- 2021/01/16 06:00 [medline] AID - 55361 [pii] AID - 10.7554/eLife.55361 [doi] PST - epublish SO - Elife. 2021 Jan 15;10:e55361. doi: 10.7554/eLife.55361. PMID- 33055079 OWN - NLM STAT- Publisher LR - 20210305 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 80 IP - 3 DP - 2020 Oct 14 TI - Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identify WNT9A as novel osteoarthritis gene. PG - 367-75 LID - annrheumdis-2020-217834 [pii] LID - 10.1136/annrheumdis-2020-217834 [doi] AB - BACKGROUND: Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology. METHODS: We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees. RESULTS: We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa, RUNX2, COL27A1, ASTN2, IL11 and GDF5 loci. CONCLUSIONS: We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes. CI - © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Boer, Cindy Germaine AU - Boer CG AUID- ORCID: 0000-0003-4809-0044 AD - Department of Internal Medicine, Genetic Laboratories, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. FAU - Yau, Michelle S AU - Yau MS AD - Hebrew SeniorLife, Beth Israel Deaconess Medical Center. Harvard Medical School, Hinda and Arthur Marcus Institute for Aging Research, Boston, Massachusetts, USA. AD - Department of Rheumatology, Boston University School of Medicine, Boston, Massachusetts, USA. FAU - Rice, Sarah J AU - Rice SJ AD - Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. FAU - Coutinho de Almeida, Rodrigo AU - Coutinho de Almeida R AUID- ORCID: 0000-0001-7966-056X AD - Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Cheung, Kathleen AU - Cheung K AD - Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. AD - Newcastle University, Bioinformatics Support Unit, Newcastle upon Tyne, UK. FAU - Styrkarsdottir, Unnur AU - Styrkarsdottir U AD - deCODE genetics/Amgen, Inc, Reykjavik, Iceland. FAU - Southam, Lorraine AU - Southam L AD - Institute of Translational Genomics, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany. FAU - Broer, Linda AU - Broer L AD - Department of Internal Medicine, Genetic Laboratories, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. FAU - Wilkinson, Jeremy Mark AU - Wilkinson JM AUID- ORCID: 0000-0001-5577-3674 AD - Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK. FAU - Uitterlinden, André G AU - Uitterlinden AG AD - Department of Internal Medicine, Genetic Laboratories, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. AD - Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. FAU - Zeggini, Eleftheria AU - Zeggini E AD - Institute of Translational Genomics, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany. FAU - Felson, David AU - Felson D AUID- ORCID: 0000-0002-2668-2447 AD - Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, UK. FAU - Loughlin, John AU - Loughlin J AD - Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. FAU - Young, Mariel AU - Young M AD - Human Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Capellini, Terence Dante AU - Capellini TD AD - Human Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Meulenbelt, Ingrid AU - Meulenbelt I AD - Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. FAU - van Meurs, Joyce Bj AU - van Meurs JB AD - Department of Internal Medicine, Genetic Laboratories, Erasmus MC, University Medical Center, Rotterdam, The Netherlands j.vanmeurs@erasmusmc.nl. LA - eng GR - HHSN268201500001C/HL/NHLBI NIH HHS/United States GR - 20771/VAC_/Versus Arthritis/United Kingdom GR - P60 AR047785/AR/NIAMS NIH HHS/United States GR - HHSN268201500001I/HL/NHLBI NIH HHS/United States GR - N01HC25195/HL/NHLBI NIH HHS/United States GR - R01 AR075356/AR/NIAMS NIH HHS/United States GR - R01 AG018393/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20201014 TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 SB - IM PMC - PMC7892373 OTO - NOTNLM OT - epidemiology OT - genetic OT - osteoarthritis OT - polymorphism COIS- Competing interests: None declared. EDAT- 2020/10/16 06:00 MHDA- 2020/10/16 06:00 CRDT- 2020/10/15 17:20 PHST- 2020/05/01 00:00 [received] PHST- 2020/09/07 00:00 [revised] PHST- 2020/09/08 00:00 [accepted] PHST- 2020/10/15 17:20 [entrez] PHST- 2020/10/16 06:00 [pubmed] PHST- 2020/10/16 06:00 [medline] AID - annrheumdis-2020-217834 [pii] AID - 10.1136/annrheumdis-2020-217834 [doi] PST - aheadofprint SO - Ann Rheum Dis. 2020 Oct 14;80(3):367-75. doi: 10.1136/annrheumdis-2020-217834.