{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:05:49Z","timestamp":1790766349258,"version":"4.1.0"},"reference-count":110,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Technology to generate single cell RNA-sequencing (scRNA-seq) datasets and tools to annotate them have advanced rapidly in the past several years. Such tools generally rely on existing transcriptomic datasets or curated databases of cell type defining genes, while the application of scalable natural language processing (NLP) methods to enhance analysis workflows has not been adequately explored. Here we deployed an NLP framework to objectively quantify associations between a comprehensive set of over 20,000 human protein-coding genes and over 500 cell type terms across over 26 million biomedical documents. The resultant gene-cell type associations (GCAs) are significantly stronger between a curated set of matched cell type-marker pairs than the complementary set of mismatched pairs (Mann Whitney p = 6.15 \u00d7 10\u221276, r = 0.24; cohen\u2019s D = 2.6). Building on this, we developed an augmented annotation algorithm (single cell Annotation via Literature Encoding, or scALE) that leverages GCAs to categorize cell clusters identified in scRNA-seq datasets, and we tested its ability to predict the cellular identity of 133 clusters from nine datasets of human breast, colon, heart, joint, ovary, prostate, skin, and small intestine tissues. With the optimized settings, the true cellular identity matched the top prediction in 59% of tested clusters and was present among the top five predictions for 91% of clusters. scALE slightly outperformed an existing method for reference data driven automated cluster annotation, and we demonstrate that integration of scALE can meaningfully improve the annotations derived from such methods. Further, contextualization of differential expression analyses with these GCAs highlights poorly characterized markers of well-studied cell types, such as CLIC6 and DNASE1L3 in retinal pigment epithelial cells and endothelial cells, respectively. Taken together, this study illustrates for the first time how the systematic application of a literature-derived knowledge graph can expedite and enhance the annotation and interpretation of scRNA-seq data.<\/jats:p>","DOI":"10.3390\/genes12060898","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T13:31:39Z","timestamp":1623331899000},"page":"898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Literature-Derived Knowledge Graph Augments the Interpretation of Single Cell RNA-seq Datasets"],"prefix":"10.3390","volume":"12","author":[{"given":"Deeksha","family":"Doddahonnaiah","sequence":"first","affiliation":[{"name":"nference, One Main Street, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1950-9179","authenticated-orcid":false,"given":"Patrick","family":"Lenehan","sequence":"additional","affiliation":[{"name":"nference, One Main Street, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Hughes","sequence":"additional","affiliation":[{"name":"nference, One Main Street, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Zemmour","sequence":"additional","affiliation":[{"name":"nference, One Main Street, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1203-2918","authenticated-orcid":false,"given":"Enrique","family":"Garcia-Rivera","sequence":"additional","affiliation":[{"name":"nference, One Main Street, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Venkatakrishnan","sequence":"additional","affiliation":[{"name":"nference, One Main Street, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramakrishna","family":"Chilaka","sequence":"additional","affiliation":[{"name":"nference Labs, Bengaluru, Karnataka 560017, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apoorv","family":"Khare","sequence":"additional","affiliation":[{"name":"nference Labs, Bengaluru, Karnataka 560017, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhil","family":"Kasaraneni","sequence":"additional","affiliation":[{"name":"nference Labs, Bengaluru, Karnataka 560017, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhinav","family":"Garg","sequence":"additional","affiliation":[{"name":"nference Labs, Bengaluru, Karnataka 560017, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akash","family":"Anand","sequence":"additional","affiliation":[{"name":"nference Labs, Bengaluru, Karnataka 560017, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Barve","sequence":"additional","affiliation":[{"name":"nference Labs, Bengaluru, Karnataka 560017, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viswanathan","family":"Thiagarajan","sequence":"additional","affiliation":[{"name":"nference Labs, Bengaluru, Karnataka 560017, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venky","family":"Soundararajan","sequence":"additional","affiliation":[{"name":"nference, One Main Street, Cambridge, MA 02142, USA"},{"name":"nference Labs, Bengaluru, Karnataka 560017, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14049","DOI":"10.1038\/ncomms14049","article-title":"Massively parallel digital transcriptional profiling of single cells","volume":"8","author":"Zheng","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/nbt.2967","article-title":"Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex","volume":"32","author":"Pollen","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.cell.2015.05.002","article-title":"Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets","volume":"161","author":"Macosko","year":"2015","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.cell.2015.04.044","article-title":"Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells","volume":"161","author":"Klein","year":"2015","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1126\/science.1247651","article-title":"Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types","volume":"343","author":"Jaitin","year":"2014","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e95","DOI":"10.1093\/nar\/gkz543","article-title":"CHETAH: A selective, hierarchical cell type identification method for single-cell RNA sequencing","volume":"47","author":"Lijnzaad","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4688","DOI":"10.1093\/bioinformatics\/btz292","article-title":"scMatch: A single-cell gene expression profile annotation tool using reference datasets","volume":"35","author":"Hou","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1038\/s41592-019-0535-3","article-title":"Supervised classification enables rapid annotation of cell atlases","volume":"16","author":"Pliner","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"490","DOI":"10.3389\/fgene.2020.00490","article-title":"SCSA: A Cell Type Annotation Tool for Single-Cell RNA-seq Data","volume":"11","author":"Cao","year":"2020","journal-title":"Front. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100882","DOI":"10.1016\/j.isci.2020.100882","article-title":"scCATCH: Automatic Annotation on Cell Types of Clusters from Single-Cell RNA Sequencing Data","volume":"23","author":"Shao","year":"2020","journal-title":"iScience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3458","DOI":"10.1038\/s41467-020-17281-7","article-title":"Searching large-scale scRNA-seq databases via unbiased cell embedding with Cell BLAST","volume":"11","author":"Cao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e9620","DOI":"10.15252\/msb.20209620","article-title":"Probabilistic harmonization and annotation of single-cell transcriptomics data with deep generative models","volume":"17","author":"Xu","year":"2021","journal-title":"Mol. Syst. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pique-Regi, R., Romero, R., Tarca, A.L., Sendler, E.D., Xu, Y., Garcia-Flores, V., Leng, Y., Luca, F., Hassan, S.S., and Gomez-Lopez, N. (2019). Single cell transcriptional signatures of the human placenta in term and preterm parturition. eLife, 8.","DOI":"10.7554\/eLife.52004"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Grive, K.J., Hu, Y., Shu, E., Grimson, A., Elemento, O., Grenier, J.K., and Cohen, P.E. (2019). Dynamic transcriptome profiles within spermatogonial and spermatocyte populations during postnatal testis maturation revealed by single-cell sequencing. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1007810"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1038\/s41467-020-16162-3","article-title":"Epithelial plasticity can generate multi-lineage phenotypes in human and murine bladder cancers","volume":"11","author":"Sfakianos","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1016\/j.cell.2020.05.017","article-title":"Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer","volume":"181","author":"Oh","year":"2020","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41586-018-0394-6","article-title":"A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte","volume":"560","author":"Plasschaert","year":"2018","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41586-018-0393-7","article-title":"A revised airway epithelial hierarchy includes CFTR-expressing ionocytes","volume":"560","author":"Montoro","year":"2018","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"R21","DOI":"10.1186\/gb-2005-6-2-r21","article-title":"An ontology for cell types","volume":"6","author":"Bard","year":"2005","journal-title":"Genome Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Meehan, T.F., Masci, A.M., Abdulla, A., Cowell, L.G., Blake, J.A., Mungall, C.J., and Diehl, A.D. (2011). Logical development of the cell ontology. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-6"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jbi.2010.01.006","article-title":"Hematopoietic cell types: Prototype for a revised cell ontology","volume":"44","author":"Diehl","year":"2011","journal-title":"J. Biomed. Inform."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D267","DOI":"10.1093\/nar\/gkh061","article-title":"The Unified Medical Language System (UMLS): Integrating biomedical terminology","volume":"32","author":"Bodenreider","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D786","DOI":"10.1093\/nar\/gky930","article-title":"Genenames.org: The HGNC and VGNC resources in 2019","volume":"47","author":"Braschi","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Venkatakrishnan, A.J., Puranik, A., Anand, A., Zemmour, D., Yao, X., Wu, X., Chilaka, R., Murakowski, D.K., Standish, K., and Raghunathan, B. (2020). Knowledge synthesis of 100 million biomedical documents augments the deep expression profiling of coronavirus receptors. eLife, 9.","DOI":"10.7554\/eLife.58040"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.cmet.2016.08.020","article-title":"Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes","volume":"24","author":"Segerstolpe","year":"2016","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41586-019-1373-2","article-title":"A human liver cell atlas reveals heterogeneity and epithelial progenitors","volume":"572","author":"Aizarani","year":"2019","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-018-0698-6","article-title":"Single-cell reconstruction of the early maternal-fetal interface in humans","volume":"563","author":"Efremova","year":"2018","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/s41591-020-0944-y","article-title":"A single-cell atlas of the peripheral immune response in patients with severe COVID-19","volume":"26","author":"Wilk","year":"2020","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"24100","DOI":"10.1073\/pnas.1914143116","article-title":"Single-cell transcriptomics of the human retinal pigment epithelium and choroid in health and macular degeneration","volume":"116","author":"Voigt","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","unstructured":"(2021, March 13). Seurat\u2014Guided Clustering Tutorial. Available online: https:\/\/satijalab.org\/seurat\/articles\/pbmc3k_tutorial.html."},{"key":"ref_32","unstructured":"(2021, March 13). 3k PBMCs from a Healthy Donor (v1), Single Cell Gene Expression Dataset by Cell Ranger 1.1.0, 10\u00d7 Genomics. Available online: https:\/\/support.10xgenomics.com\/single-cell-gene-expression\/datasets\/1.1.0\/pbmc3k?."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/s41591-019-0468-5","article-title":"A cellular census of human lungs identifies novel cell states in health and in asthma","volume":"25","author":"Kar","year":"2019","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Franz\u00e9n, O., Gan, L.-M., and Bj\u00f6rkegren, J.L.M. (2019). PanglaoDB: A web server for exploration of mouse and human single-cell RNA sequencing data. Database, 2019.","DOI":"10.1093\/database\/baz046"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.stem.2016.05.010","article-title":"De Novo Prediction of Stem Cell Identity using Single-Cell Transcriptome Data","volume":"19","author":"Muraro","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.cels.2016.09.002","article-title":"A Single-Cell Transcriptome Atlas of the Human Pancreas","volume":"3","author":"Muraro","year":"2016","journal-title":"Cell Syst."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4902","DOI":"10.1038\/s41467-019-12780-8","article-title":"Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration","volume":"10","author":"Menon","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1164\/rccm.201911-2199OC","article-title":"A Single-Cell Atlas of the Human Healthy Airways","volume":"202","author":"Deprez","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/s41586-019-1631-3","article-title":"Resolving the fibrotic niche of human liver cirrhosis at single-cell level","volume":"575","author":"Ramachandran","year":"2019","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1126\/science.aat5031","article-title":"Spatiotemporal immune zonation of the human kidney","volume":"365","author":"Stewart","year":"2019","journal-title":"Science"},{"key":"ref_41","unstructured":"(2019, September 01). Immune Cell Atlas: Blood Mononuclear Cells (2 Donors, 2 Sites). Available online: https:\/\/singlecell.broadinstitute.org\/single_cell\/study\/SCP345\/ica-blood-mononuclear-cells-2-donors-2-sites."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-019-1906-x","article-title":"scRNA-seq assessment of the human lung, spleen, and esophagus tissue stability after cold preservation","volume":"21","author":"Madissoon","year":"2019","journal-title":"Genome Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Shih, A.J., Menzin, A., Whyte, J., Lovecchio, J., Liew, A., Khalili, H., Bhuiya, T., Gregersen, P.K., and Lee, A.T. (2018). Identification of grade and origin specific cell populations in serous epithelial ovarian cancer by single cell RNA-seq. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0206785"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.molcel.2018.10.029","article-title":"Transcriptome landscape of human folliculogenesis reveals oocyte and granulosa cell interactions","volume":"72","author":"Zhang","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"jem.20191130","DOI":"10.1084\/jem.20191130","article-title":"Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine","volume":"217","author":"Wang","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1016\/j.cell.2017.10.044","article-title":"Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer","volume":"171","author":"Puram","year":"2017","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41422-018-0099-2","article-title":"The adult human testis transcriptional cell atlas","volume":"28","author":"Guo","year":"2018","journal-title":"Cell Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41593-020-0587-9","article-title":"Single-cell analysis of olfactory neurogenesis and differentiation in adult humans","volume":"23","author":"Durante","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1681\/ASN.2019040335","article-title":"Single-cell transcriptomic map of the human and mouse bladders","volume":"30","author":"Yu","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s42255-019-0152-6","article-title":"Single-cell analysis of human adipose tissue identifies depot and disease specific cell types","volume":"2","author":"Vijay","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41586-020-2157-4","article-title":"Construction of a human cell landscape at single-cell level","volume":"581","author":"Han","year":"2020","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.cels.2016.08.011","article-title":"A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intra-cell Population Structure","volume":"3","author":"Baron","year":"2016","journal-title":"Cell Syst."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/nmeth.4407","article-title":"Massively parallel single-nucleus RNA-seq with DroNc-seq","volume":"14","author":"Habib","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/s41590-020-0602-z","article-title":"Distinct microbial and immune niches of the human colon","volume":"21","author":"James","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4383","DOI":"10.1038\/s41467-018-06318-7","article-title":"Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations","volume":"9","author":"MacParland","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/s41586-019-1652-y","article-title":"Decoding human fetal liver haematopoiesis","volume":"574","author":"Popescu","year":"2019","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"E12363","DOI":"10.1073\/pnas.1813819115","article-title":"Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue","volume":"115","author":"Zanini","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/j.cell.2020.05.006","article-title":"Host-viral infection maps reveal signatures of severe COVID-19 patients","volume":"181","author":"Bost","year":"2020","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.cell.2020.04.035","article-title":"SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues","volume":"181","author":"Ziegler","year":"2020","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/s41587-020-0602-4","article-title":"COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis","volume":"38","author":"Chua","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"15081","DOI":"10.1038\/ncomms15081","article-title":"Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer","volume":"8","author":"Chung","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3588","DOI":"10.1038\/s41467-018-06052-0","article-title":"Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq","volume":"9","author":"Karaayvaz","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/s41467-019-08595-2","article-title":"Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer","volume":"10","author":"Merino","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1016\/j.celrep.2019.04.052","article-title":"Dissecting the Single-Cell Transcriptome Network Underlying Gastric Premalignant Lesions and Early Gastric Cancer","volume":"27","author":"Zhang","year":"2019","journal-title":"Cell Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.ccell.2020.01.003","article-title":"The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal Fallopian tube epithelial cells","volume":"37","author":"Hu","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1126\/science.aab0917","article-title":"RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance","volume":"349","author":"Miyamoto","year":"2015","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/s41422-020-0355-0","article-title":"A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling","volume":"30","author":"Qian","year":"2020","journal-title":"Cell Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/s41467-019-14256-1","article-title":"Single-cell analysis reveals new evolutionary complexity in uveal melanoma","volume":"11","author":"Durante","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cels.2018.11.005","article-title":"Scrublet: Computational identification of cell Doublets in Single-cell transcriptomic data","volume":"8","author":"Wolock","year":"2019","journal-title":"Cell Syst."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.cell.2018.05.060","article-title":"Single-cell map of diverse immune phenotypes in the breast tumor microenvironment","volume":"174","author":"Azizi","year":"2018","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.cell.2019.06.029","article-title":"Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis","volume":"178","author":"Smillie","year":"2019","journal-title":"Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/s41556-019-0446-7","article-title":"Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function","volume":"22","author":"Wang","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"10868","DOI":"10.1038\/s41598-020-67730-y","article-title":"Synovial cell cross-talk with cartilage plays a major role in the pathogenesis of osteoarthritis","volume":"10","author":"Chou","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1038\/s41467-019-11036-9","article-title":"Single-cell reconstruction of follicular remodeling in the human adult ovary","volume":"10","author":"Fan","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1016\/j.celrep.2018.11.086","article-title":"A Cellular Anatomy of the Normal Adult Human Prostate and Prostatic Urethra","volume":"25","author":"Henry","year":"2018","journal-title":"Cell Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.celrep.2018.09.006","article-title":"Transcriptional programming of normal and inflamed human epidermis at single-cell resolution","volume":"25","author":"Cheng","year":"2018","journal-title":"Cell Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.cell.2019.08.008","article-title":"Single-Cell Analysis of Crohn\u2019s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy","volume":"178","author":"Martin","year":"2019","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"The Tabula Muris Consortium, Pisco, A.O., Schaum, N., McGeever, A., Karkanias, J., Neff, N.F., Darmanis, S., Wyss-Coray, T., and Quake, S.R. (2020). A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature, 583, 590\u2013595.","DOI":"10.1038\/s41586-020-2496-1"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature24489","article-title":"A single-cell survey of the small intestinal epithelium","volume":"551","author":"Haber","year":"2017","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.cell.2018.02.001","article-title":"Mapping the mouse cell atlas by Microwell-seq","volume":"172","author":"Han","year":"2018","journal-title":"Cell"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Rajbhandari, P., Arneson, D., Hart, S.K., Ahn, I.S., Diamante, G., Santos, L.C., Zaghari, N., Feng, A.-C., Thomas, B.J., and Vergnes, L. (2019). Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes. eLife, 8.","DOI":"10.7554\/eLife.49501"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/s41467-019-08831-9","article-title":"An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics","volume":"10","author":"Angelidis","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"5150","DOI":"10.1038\/s41467-018-07582-3","article-title":"Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing","volume":"9","author":"Bartoschek","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"D794","DOI":"10.1093\/nar\/gkx1081","article-title":"The Encyclopedia of DNA elements (ENCODE): Data portal update","volume":"46","author":"Davis","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_87","unstructured":"R Core Team (2020). R Core Team R: A Language and Environment for Statistical Computing, R Core Team."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Park, J., Marquez, A.L., Puranik, A., Rajasekharan, A., Aravamudan, M., and Garcia-Rivera, E. (2019). Recapitulation and Retrospective Prediction of Biomedical Associations Using Temporally-enabled Word Embeddings. bioRxiv, 627513.","DOI":"10.1101\/627513"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.1073\/pnas.95.6.3088","article-title":"Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis","volume":"95","author":"Morimura","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ajoc.2016.03.005","article-title":"Retinitis pigmentosa associated with a mutation in BEST1","volume":"2","author":"Dalvin","year":"2016","journal-title":"Am. J. Ophthalmol. Case Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1167\/iovs.61.13.9","article-title":"Partially differentiated neuroretinal cells promote maturation of the retinal pigment epithelium","volume":"61","author":"Singh","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Booij, J.C., ten Brink, J.B., Swagemakers, S.M.A., Verkerk, A.J.M.H., Essing, A.H.W., van der Spek, P.J., and Bergen, A.A.B. (2010). A new strategy to identify and annotate human RPE-specific gene expression. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009341"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1001\/jamaophthalmol.2014.2065","article-title":"Proteomic landscape of the human choroid-retinal pigment epithelial complex","volume":"132","author":"Skeie","year":"2014","journal-title":"JAMA Ophthalmol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6016","DOI":"10.1038\/s41598-017-06233-9","article-title":"Comparative proteomic analysis of human embryonic stem cell-derived and primary human retinal pigment epithelium","volume":"7","author":"Hongisto","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.ajhg.2020.09.006","article-title":"Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction","volume":"107","author":"Chan","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.cell.2016.05.034","article-title":"Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity","volume":"166","author":"Sisirak","year":"2016","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1038\/ng.975","article-title":"Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus","volume":"43","author":"Sunker","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Jamil, M.A., Singer, H., Al-Rifai, R., N\u00fcsgen, N., Rath, M., Strauss, S., Andreou, I., Oldenburg, J., and El-Maarri, O. (2020). Molecular Analysis of Fetal and Adult Primary Human Liver Sinusoidal Endothelial Cells: A Comparison to Other Endothelial Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207776"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41419-020-03356-2","article-title":"PU.1 drives specification of pluripotent stem cell-derived endothelial cells to LSEC-like cells","volume":"12","author":"Talon","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2832","DOI":"10.1038\/s41467-019-10861-2","article-title":"A single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys","volume":"10","author":"Lake","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1046\/j.1365-2249.2003.02267.x","article-title":"Dnase1l3 deficiency in lupus-prone MRL and NZB\/W F1 mice","volume":"134","author":"Wilber","year":"2003","journal-title":"Clin. Exp. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ajhg.2013.12.002","article-title":"Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis","volume":"94","author":"Mayes","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1002\/art.38010","article-title":"DNASE1L3 mutations in hypocomplementemic urticarial vasculitis syndrome","volume":"65","author":"Foster","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Svensson, V., da Veiga Beltrame, E., and Pachter, L. (2020). A curated database reveals trends in single-cell transcriptomics. Database, 2020.","DOI":"10.1093\/database\/baaa073"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0378-1119(03)00830-8","article-title":"Identification of a novel member of the CLIC family, CLIC6, mapping to 21q22.12","volume":"320","author":"Friedli","year":"2003","journal-title":"Gene"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"11164","DOI":"10.1074\/jbc.275.15.11164","article-title":"Molecular cloning and characterization of a novel chloride intracellular channel-related protein, parchorin, expressed in water-secreting cells","volume":"275","author":"Nishizawa","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0169-328X(03)00283-3","article-title":"CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors","volume":"117","author":"Griffon","year":"2003","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1091\/mbc.e09-10-0907","article-title":"Chloride intracellular channel 4 is critical for the epithelial morphogenesis of RPE cells and retinal attachment","volume":"21","author":"Chuang","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"12247","DOI":"10.1038\/s41598-019-48438-0","article-title":"CLIC4 regulates late endosomal trafficking and matrix degradation activity of MMP14 at focal adhesions in RPE cells","volume":"9","author":"Hsu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"6882","DOI":"10.1038\/s41598-018-25231-z","article-title":"Inherent flexibility of CLIC6 revealed by crystallographic and solution studies","volume":"8","author":"Ferofontov","year":"2018","journal-title":"Sci. Rep."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/6\/898\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:12:51Z","timestamp":1760163171000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/6\/898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,10]]},"references-count":110,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["genes12060898"],"URL":"https:\/\/doi.org\/10.3390\/genes12060898","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.04.01.438124","asserted-by":"object"}]},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,10]]}}}