Revealing the Critical Regulators of Cell Identity in the Mouse Cell Atlas

SUMMARY Recent progress in single-cell technologies has enabled the identification of all major cell types in mouse. However, for most cell types, the regulatory mechanism underlying their identity remains poorly understood. By computational analysis of the recently published mouse cell atlas data, we have identified 202 regulons whose activities are highly variable across different cell types, and more importantly, predicted a small set of essential regulators for each major cell type in mouse. Systematic validation by automated literature and data mining provides strong additional support for our predictions. Thus, these predictions serve as a valuable resource that would be useful for the broad biological community. Finally, we have built a user-friendly, interactive web portal to enable users to navigate this mouse cell network atlas.

[1]  Hiroshi Sekiya,et al.  Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation , 2009, Nature Cell Biology.

[2]  R. Matusik,et al.  NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. , 2014, Molecular endocrinology.

[3]  Stijn van Dongen,et al.  Using MCL to extract clusters from networks. , 2012, Methods in molecular biology.

[4]  S. Brody,et al.  Epithelial c-jun and c-fos are temporally and spatially regulated by estradiol during neonatal rat oviduct differentiation. , 2004, The Journal of endocrinology.

[5]  Hao Wang,et al.  Global regulation of erythroid gene expression by transcription factor GATA-1. , 2004, Blood.

[6]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[7]  C. Myers,et al.  Using networks to measure similarity between genes: association index selection , 2013, Nature Methods.

[8]  Takuro Nakamura,et al.  Bcl11a is essential for normal lymphoid development , 2003, Nature Immunology.

[9]  S Miyano,et al.  Open source clustering software. , 2004, Bioinformatics.

[10]  S. Brody,et al.  Transcriptional Regulation of an Axonemal Central Apparatus Gene, Sperm-associated Antigen 6, by a SRY-related High Mobility Group Transcription Factor, S-SOX5 , 2010, The Journal of Biological Chemistry.

[11]  M. Moser,et al.  STAT5 Is an Ambivalent Regulator of Neutrophil Homeostasis , 2007, PloS one.

[12]  James T. Webber,et al.  Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris , 2018, Nature.

[13]  S. Aerts,et al.  Mapping gene regulatory networks from single-cell omics data , 2018, Briefings in functional genomics.

[14]  Jun Luo,et al.  Peroxisome proliferator-activated receptor delta facilitates lipid secretion and catabolism of fatty acids in dairy goat mammary epithelial cells. , 2017, Journal of dairy science.

[15]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[16]  S. Orkin,et al.  Mapping the Mouse Cell Atlas by Microwell-Seq , 2018, Cell.

[17]  Allon M. Klein,et al.  Single-cell mapping of gene expression landscapes and lineage in the zebrafish embryo , 2018, Science.

[18]  Ken-ichi Inoue,et al.  Expression profile of urothelial transcription factors in bladder biopsies with interstitial cystitis , 2017, International journal of urology : official journal of the Japanese Urological Association.

[19]  C. Steidl,et al.  Fine-tuning of FOXO3A in cHL as a survival mechanism and a hallmark of abortive plasma cell differentiation. , 2018, Blood.

[20]  A. Pierani,et al.  Requirement for RORgamma in thymocyte survival and lymphoid organ development. , 2000, Science.

[21]  Michael J. T. Stubbington,et al.  Single-cell transcriptomics to explore the immune system in health and disease , 2017, Science.

[22]  L. Zon,et al.  Hematopoiesis: An Evolving Paradigm for Stem Cell Biology , 2008, Cell.

[23]  Cole Trapnell,et al.  Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. , 2011, Genes & development.

[24]  Fabian J Theis,et al.  Cell type atlas and lineage tree of a whole complex animal by single-cell transcriptomics , 2018, Science.

[25]  S. Orkin,et al.  Reprogramming Committed Murine Blood Cells to Induced Hematopoietic Stem Cells with Defined Factors , 2014, Cell.

[26]  Nan Qiao,et al.  CoCiter: An Efficient Tool to Infer Gene Function by Assessing the Significance of Literature Co-Citation , 2013, PloS one.

[27]  F. Borràs,et al.  Transcription factors that regulate monocyte/macrophage differentiation , 1998, Journal of leukocyte biology.

[28]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[29]  W. Ouwehand,et al.  Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. , 2010, Cell stem cell.

[30]  V. Vedantham,et al.  Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors , 2010, Cell.

[31]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[32]  Darwin J. Prockop,et al.  Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice , 2006, Proceedings of the National Academy of Sciences.

[33]  Evan Z. Macosko,et al.  Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain , 2018, Cell.

[34]  Omri Wurtzel,et al.  Cell type transcriptome atlas for the planarian Schmidtea mediterranea , 2018, Science.

[35]  Principal Investigators,et al.  Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris , 2018 .

[36]  M. Birrer,et al.  c-Jun triggers apoptosis in human vascular endothelial cells. , 1999, Circulation research.

[37]  R. Mason.  Biology of alveolar type II cells , 2006, Respirology.

[38]  Alok J. Saldanha,et al.  Java Treeview - extensible visualization of microarray data , 2004, Bioinform..

[39]  J. Aerts,et al.  SCENIC: Single-cell regulatory network inference and clustering , 2017, Nature Methods.

[40]  Andrew C. Adey,et al.  Single-Cell Transcriptional Profiling of a Multicellular Organism , 2017 .

[41]  Rudolf Grosschedl,et al.  Transcription factor EBF1 is essential for the maintenance of B cell identity and prevention of alternative fates in committed cells , 2013, Nature Immunology.

[42]  P. Verstreken,et al.  A Single-Cell Transcriptome Atlas of the Aging Drosophila Brain , 2018, Cell.

[43]  Ellen V. Rothenberg,et al.  Developmental gene networks: a triathlon on the course to T cell identity , 2014, Nature Reviews Immunology.

[44]  Ross C. Hardison,et al.  Dynamic shifts in occupancy by TAL1 are guided by GATA factors and drive large-scale reprogramming of gene expression during hematopoiesis , 2014, Genome research.

[45]  Kai Li,et al.  Targeted exploration and analysis of large cross-platform human transcriptomic compendia , 2015, Nature Methods.

[46]  J. Cowland,et al.  The in vivo profile of transcription factors during neutrophil differentiation in human bone marrow. , 2003, Blood.

[47]  J. Zuchero,et al.  Intrinsic and extrinsic control of oligodendrocyte development , 2013, Current Opinion in Neurobiology.

[48]  Richard A. Muscat,et al.  Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding , 2018, Science.

[49]  Dong Wook Han,et al.  Direct reprogramming of fibroblasts into neural stem cells by defined factors. , 2012, Cell stem cell.

[50]  T. Matsuda,et al.  Restricted expression of Ovol2/MOVO in XY body of mouse spermatocytes at the pachytene stage. , 2012, Journal of andrology.

[51]  Geoffrey E. Hinton,et al.  Visualizing Data using t-SNE , 2008 .

[52]  M. Tschan,et al.  TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial-mesenchymal transition-like tumor budding phenotype in colorectal cancer , 2014, Oncotarget.

[53]  Lars E. Borm,et al.  Molecular Architecture of the Mouse Nervous System , 2018, Cell.

[54]  T. Graf,et al.  Distinct C/EBP functions are required for eosinophil lineage commitment and maturation. , 1998, Genes & development.

[55]  Fabian J Theis,et al.  The Human Cell Atlas , 2017, bioRxiv.

[56]  S. Teichmann,et al.  Exponential scaling of single-cell RNA-seq in the past decade , 2017, Nature Protocols.

[57]  A. Regev,et al.  The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells , 2014, Nature Immunology.