Cytomics Reactome. The trillions of cells in the adult human body, specialized to fulfill diverse roles in tissues, organs, and organ systems, all originate from a single cell, a zygote formed at conception. From zygote to adulthood, cells divide and commit to different fates. The steps from a pluripotent stem cell to a specialized descendant constitute a cell lineage path. Cytomics Reactome extends the data structure used for molecular-level annotation of cell biology to annotate cell lineage paths, organizing them by organ systems, cross-referencing them to Gene Ontology biological processes, and dividing each into causally connected cell development steps. These reaction-like steps describe transitions between cell states during development or differentiation, characterized by positive and negative regulators and required input components (cell state biomarkers required for the action of regulators). Each cell state corresponds to a unique combination of cell type (Cell Ontology), anatomical location (UBERON), and protein and/or RNA markers, as described in the Cytomics section of the  User Guide. Recently developed tools that harvest omics data from single cells of multicellular organisms and track fates open the door to deciphering cell lineage paths at single-cell resolution, a critical requirement of regenerative medicine and cancer medicine. Cytomics Reactome is intended to support such technologies and their application to human biology as they emerge.

The first Cytomics cell lineage path, Differentiation of keratinocytes in interfollicular epidermis in mammalian skin, describes the differentiation of keratinocytes from stem cells to corneocytes in the interfollicular epidermis, the skin surface layer in between the adnexa (hair follicles, sweat glands, and sebaceous glands). The path is described in four cell differentiation steps involving five distinct cellular states: keratinocyte stem cells of the epidermal basal layer, transit amplifying cells, spinous keratinocytes, granular keratinocytes, and corneocytes. Each differentiation step is regulated by a distinct combination of regulatory molecules present in the microenvironments of the differentiating cells.

New and Updated Topics and Pathways. Topics with new or revised pathways in this release include Cell Cycle (Resolution of Sister Chromatid Cohesion), Developmental Biology (Differentiation of keratinocytes in intefrollicular skin epidermis, MITF-M-regulation melanocyte development, Transcriptional regulation of brown and beige adipocyte differentiation), Disease (Defective regulation of TLR by endogenous ligand, Signaling by LTK in cancer), Immune System (Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE), Regulation of TLR by endogenous ligand, TICAM1-dependent activation of IRF3/IRF7 ), Metabolism (Acetylcholine regulates insulin secretion, Adrenaline,noradrenaline inhibits insulin secretion, Aerobic respiration and respiratory electron transport, AMPK inhibits chREBP transcriptional activation activity, Branched-chain amino acid catabolism, ChREBP activates metabolic gene expression, Citric acid cycle (TCA cycle), Glucagon signaling in metabolic regulation, Glucagon-like Peptide-1 (GLP1) regulates insulin secretion, Heme biosynthesis, Malate-aspartate shuttle, Maturation of TCA enzymes and regulation of TCA cycle, NADPH regeneration, PI and PC transport between ER and Golgi membranes, PKA-mediated phosphorylation of key metabolic factors, Pyruvate metabolism, Regulation of pyruvate dehydrogenase (PDH) complex, Respiratory electron transport), Metabolism of proteins (Protein lipoylation), Signal Transduction (EGFR Transactivation by Gastrin, Signaling by LTK), Transport of small molecules (Iron uptake and transport).

New and Updated Illustrations.  New or revised Illustrations with embedded navigation features have been created for Adipogenesis, Developmental Biology, Developmental Cell Lineages, Diseases associated with TLR signaling cascade, Diseases of signal transduction by growth factor receptors and second messengers, Metabolism, MITF-M-regulated melanocyte development, Post-translational protein modification, and Signalling by Receptor Tyrosine Kinases. A new static illustration is available for Respiratory syncytial virus (RSV) attachment and entry.

Thanks to our Contributors.   Tae-Hwa Chun, Toni Franjkić, Clarisse Ganier, Heinz Arnheiter, David Hill, Xing Liu, Ivana Munitic, and Xuebiao Yao are our external reviewers.

Annotation Statistics. Reactome comprises 15,212 human reactions organized into 2,698  pathways involving 30585 proteins and modified forms of proteins encoded by 11226 different human genes,  14789 complexes, 2128 small molecules, and 1047 drugs. These annotations are supported by 38549  literature references. We have projected these reactions onto 79407 orthologous proteins, creating 19520 orthologous pathways in 14 non-human species. Version 88 has annotations for 4944 protein variants (mutated proteins) and their post-translationally modified forms, derived from  359 proteins, which have contributed to the annotation of 1802 disease-specific reactions and 725 pathways. 

Tools and Data. Our services and software tools are designed for biologists, bioinformaticians, and software developers. Pathway data is available to view in our Pathway Browser, to analyze your own dataset, to download, and access programmatically through our Content and Analysis Services. The ReactomeFIViz app and ReactomeGSA package provide tools for multi-omics data analysis. The idg.reactome.org Web Portal provides a collection of web-based tools to help researchers place understudied proteins in a pathway context. 

Documentation and Training. Visit our online User Guide to access documentation supporting pathway analysis of experimental data. The Developer's Zone provides detailed documentation regarding our software, tools, and web services. Training and learning materials can be found here.

About the Reactome Project. Reactome is a collaboration between groups at the Ontario Institute for Cancer Research, Oregon Health and Science University, New York University Langone Medical Center, and The EMBL - European Bioinformatics Institute. Reactome is an ELIXIR Core Data Resource as well as a Global Core Biodata Resource. Reactome annotation files and interaction data derived from Reactome are distributed under a Creative Commons Public Domain (CC0 1.0 Universal) Licence. A Creative Commons Attribution 4.0 International (CC BY 4.0) Licence applies to all software and code, database data dumps, Pathway Illustrations (Enhanced High-Level Diagrams), Icon Library, Art, and Branding Materials. A full description of the new and updated content is available on the Reactome website.

Follow us on Twitter: @reactome to get frequent updates about new and updated pathways, feature updates, and more!

For more information: If you have a question, want to provide feedback, or are interested in collaborating with us to annotate a topic, please contact us at This email address is being protected from spambots. You need JavaScript enabled to view it..