Computational Tools for Stem Cell Biology.

For over half a century, the field of developmental biology has leveraged computation to explore mechanisms of developmental processes. More recently, computational approaches have been critical in the translation of high throughput data into knowledge of both developmental and stem cell biology. In the past several years, a new subdiscipline of computational stem cell biology has emerged that synthesizes the modeling of systems-level aspects of stem cells with high-throughput molecular data. In this review, we provide an overview of this new field and pay particular attention to the impact that single cell transcriptomics is expected to have on our understanding of development and our ability to engineer cell fate.

[1]  Samantha A. Morris,et al.  Dissecting Engineered Cell Types and Enhancing Cell Fate Conversion via CellNet , 2014, Cell.

[2]  Christopher P. Lapointe,et al.  RNA regulatory networks diversified through curvature of the PUF protein scaffold , 2015, Nature Communications.

[3]  K. Hochedlinger,et al.  The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming. , 2013, Cell stem cell.

[4]  S. Hoerstrup,et al.  Non-integrating episomal plasmid-based reprogramming of human amniotic fluid stem cells into induced pluripotent stem cells in chemically defined conditions , 2016, Cell cycle.

[5]  Blagoy Blagoev,et al.  Mechanism of Divergent Growth Factor Effects in Mesenchymal Stem Cell Differentiation , 2005, Science.

[6]  Michael J. Ziller,et al.  Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines , 2011, Cell.

[7]  J. Till,et al.  A STOCHASTIC MODEL OF STEM CELL PROLIFERATION, BASED ON THE GROWTH OF SPLEEN COLONY-FORMING CELLS. , 1964, Proceedings of the National Academy of Sciences of the United States of America.

[8]  A. Turing.  The chemical basis of morphogenesis , 1952, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.

[9]  Chad A. Cowan,et al.  Marked differences in differentiation propensity among human embryonic stem cell lines , 2008, Nature Biotechnology.

[10]  George M. Church,et al.  Highly Multiplexed Subcellular RNA Sequencing in Situ , 2014, Science.

[11]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[12]  N. Neff,et al.  Reconstructing lineage hierarchies of the distal lung epithelium using single cell RNA-seq , 2014, Nature.

[13]  John A Wolf,et al.  Transcriptome In Vivo Analysis (TIVA) of spatially defined single cells in intact live mouse and human brain tissue , 2014, Nature Methods.

[14]  D. Srivastava,et al.  Reprogramming of mouse fibroblasts into cardiomyocyte-like cells in vitro , 2013, Nature Protocols.

[15]  Ben D. MacArthur,et al.  Statistical Mechanics of Pluripotency , 2013, Cell.

[16]  Ron Shamir,et al.  Comprehensive MicroRNA Profiling Reveals a Unique Human Embryonic Stem Cell Signature Dominated by a Single Seed Sequence , 2008, Stem cells.

[17]  Kun Zhang,et al.  Fluorescent in situ sequencing (FISSEQ) of RNA for gene expression profiling in intact cells and tissues , 2015, Nature Protocols.

[18]  Fabian J. Theis,et al.  Characterisation of transcriptional networks in blood stem and progenitor cells using high-throughput single cell gene expression analysis , 2013, Nature Cell Biology.

[19]  Shawn M. Gillespie,et al.  Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma , 2014, Science.

[20]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[21]  A. Maitra,et al.  A molecular scheme for improved characterization of human embryonic stem cell lines , 2006, BMC Biology.

[22]  Jeroen Krijgsveld,et al.  The RNA-binding protein repertoire of embryonic stem cells , 2013, Nature Structural &Molecular Biology.

[23]  M. Gerstein,et al.  Somatic copy-number mosaicism in human skin revealed by induced pluripotent stem cells , 2012, Nature.

[24]  Eric S. Lander,et al.  Dissecting direct reprogramming through integrative genomic analysis , 2008, Nature.

[25]  I. Macaulay,et al.  Single Cell Genomics: Advances and Future Perspectives , 2014, PLoS genetics.

[26]  Patrick S. Stumpf,et al.  Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity , 2012, Nature Cell Biology.

[27]  Ira M. Hall,et al.  Genome sequencing of mouse induced pluripotent stem cells reveals retroelement stability and infrequent DNA rearrangement during reprogramming. , 2011, Cell stem cell.

[28]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[29]  Yoosik Kim,et al.  LIN28A Is a Suppressor of ER-Associated Translation in Embryonic Stem Cells , 2012, Cell.

[30]  Allon M. Klein,et al.  Droplet Barcoding for Single-Cell Transcriptomics Applied to Embryonic Stem Cells , 2015, Cell.

[31]  Sally Temple,et al.  A Systematic Approach to Identify Candidate Transcription Factors that Control Cell Identity , 2015, Stem cell reports.

[32]  D. Tenen,et al.  Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Nicholas T. Ingolia,et al.  Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes , 2011, Cell.

[34]  Grace X. Y. Zheng,et al.  Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs , 2010, Nature Structural &Molecular Biology.

[35]  Aleksandra A. Kolodziejczyk,et al.  Single Cell RNA-Sequencing of Pluripotent States Unlocks Modular Transcriptional Variation , 2015, Cell stem cell.

[36]  Nicholas T. Ingolia,et al.  Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling , 2009, Science.

[37]  Alex A. Pollen,et al.  Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex , 2014, Nature Biotechnology.

[38]  A. Mortazavi,et al.  Genome-Wide Mapping of in Vivo Protein-DNA Interactions , 2007, Science.

[39]  Colin N. Dewey,et al.  Initial sequencing and comparative analysis of the mouse genome. , 2002 .

[40]  Yong Zhang,et al.  Identifying ChIP-seq enrichment using MACS , 2012, Nature Protocols.

[41]  J. Stamatoyannopoulos,et al.  Chromatin accessibility pre-determines glucocorticoid receptor binding patterns , 2011, Nature Genetics.

[42]  W. Engel,et al.  Generation and Characterization of Yeast Two-Hybrid cDNA Libraries Derived From Two Distinct Mouse Pluripotent Cell Types , 2012, Molecular Biotechnology.

[43]  K. Helin,et al.  Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation , 2013, Nature Cell Biology.

[44]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

[45]  G. Boucher,et al.  RNA-seq analysis of 2 closely related leukemia clones that differ in their self-renewal capacity. , 2011, Blood.

[46]  Nathan C. Sheffield,et al.  The accessible chromatin landscape of the human genome , 2012, Nature.

[47]  N. Benvenisty,et al.  TeratoScore: Assessing the Differentiation Potential of Human Pluripotent Stem Cells by Quantitative Expression Analysis of Teratomas , 2015, Stem cell reports.

[48]  Michael J. Ziller,et al.  Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells , 2013, Cell.

[49]  Terrence S. Furey,et al.  F-Seq: a feature density estimator for high-throughput sequence tags , 2008, Bioinform..

[50]  K. Hochedlinger,et al.  Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells , 2010, Nature Biotechnology.

[51]  Sean C. Bendall,et al.  Single-Cell Trajectory Detection Uncovers Progression and Regulatory Coordination in Human B Cell Development , 2014, Cell.

[52]  X. Chen,et al.  The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells , 2006, Nature Genetics.

[53]  David L. A. Wood,et al.  Small RNA changes en route to distinct cellular states of induced pluripotency , 2014, Nature Communications.

[54]  Fidencio J. Neri,et al.  Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution , 2014, Science.

[55]  James J. Collins,et al.  Epigenetic Landscapes Explain Partially Reprogrammed Cells and Identify Key Reprogramming Genes , 2012, PLoS Comput. Biol..

[56]  Grace X. Y. Zheng,et al.  Erratum: Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs (Nature Structural and Molecular Biology (2011) 18 (237-244)) , 2011 .

[57]  P. Cahan,et al.  Origins and implications of pluripotent stem cell variability and heterogeneity , 2013, Nature Reviews Molecular Cell Biology.

[58]  S. Eddy,et al.  Transcription Factors That Convert Adult Cell Identity Are Differentially Polycomb Repressed , 2013, PloS one.

[59]  T. Graf,et al.  Heterogeneity of embryonic and adult stem cells. , 2008, Cell stem cell.

[60]  David W. Nauen,et al.  Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis. , 2015, Cell stem cell.

[61]  R. Stewart,et al.  Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells , 2011, Nature.

[62]  Aviv Regev,et al.  Deconstructing transcriptional heterogeneity in pluripotent stem cells , 2014, Nature.

[63]  Bernhard M. Schuldt,et al.  A bioinformatic assay for pluripotency in human cells , 2011, Nature Methods.

[64]  E. Davidson,et al.  Gene Regulatory Networks and the Evolution of Animal Body Plans , 2006, Science.

[65]  Gene W. Yeo,et al.  LIN-28 co-transcriptionally binds primary let-7 to regulate miRNA maturation in C. elegans , 2011, Nature Structural &Molecular Biology.

[66]  Evan Z. Macosko,et al.  Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets , 2015, Cell.

[67]  Megan F. Cole,et al.  Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells , 2005, Cell.

[68]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  S. Orkin,et al.  Mapping cellular hierarchy by single-cell analysis of the cell surface repertoire. , 2013, Cell stem cell.

[70]  J. Goeman,et al.  KeyGenes, a Tool to Probe Tissue Differentiation Using a Human Fetal Transcriptional Atlas , 2015, Stem cell reports.

[71]  Cole Trapnell,et al.  The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells , 2014, Nature Biotechnology.

[72]  G. Ruvkun,et al.  Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans , 1993, Cell.

[73]  Hans Clevers,et al.  Single-cell messenger RNA sequencing reveals rare intestinal cell types , 2015, Nature.

[74]  H. Ng,et al.  Uniform, optimal signal processing of mapped deep-sequencing data , 2013, Nature Biotechnology.

[75]  D. Melton,et al.  An improved ScoreCard to assess the differentiation potential of human pluripotent stem cells , 2015, Nature Biotechnology.

[76]  Howard Y. Chang,et al.  Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells , 2015, Nature.

[77]  P. Reddien,et al.  Single-cell analysis reveals functionally distinct classes within the planarian stem cell compartment. , 2014, Cell stem cell.

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

[79]  Hossein Baharvand,et al.  Proteomic signature of human embryonic stem cells , 2006, Proteomics.

[80]  D. Gifford,et al.  Analysis of the mouse embryonic stem cell regulatory networks obtained by ChIP-chip and ChIP-PET , 2008, Genome Biology.

[81]  Martin J. Aryee,et al.  Epigenetic memory in induced pluripotent stem cells , 2010, Nature.

[82]  Ilya Shmulevich,et al.  Gene pair signatures in cell type transcriptomes reveal lineage control , 2013, Nature Methods.

[83]  Rafael A Irizarry,et al.  Comprehensive high-throughput arrays for relative methylation (CHARM). , 2008, Genome research.

[84]  Vijay K. Tiwari,et al.  Genomic Prevalence of Heterochromatic H3K9me2 and Transcription Do Not Discriminate Pluripotent from Terminally Differentiated Cells , 2011, PLoS genetics.

[85]  E. Kirkness,et al.  Somatic coding mutations in human induced pluripotent stem cells , 2011, Nature.

[86]  Jay R. Hesselberth,et al.  Genome‐Wide Analysis of miRNA‐mRNA Interactions in Marrow Stromal Cells , 2014, Stem cells.

[87]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[88]  Yi Xing,et al.  m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. , 2014, Cell stem cell.

[89]  M. Kupiec,et al.  Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq , 2012, Nature.

[90]  Arthur D Lander,et al.  Morpheus Unbound: Reimagining the Morphogen Gradient , 2007, Cell.

[91]  R. Puri,et al.  Gene expression in human embryonic stem cell lines: unique molecular signature. , 2004, Blood.

[92]  Max Endele,et al.  Quantitative single-cell approaches to stem cell research. , 2014, Cell stem cell.

[93]  Rong Wang,et al.  Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming. , 2015, Cell stem cell.

[94]  Yoshihide Hayashizaki,et al.  A predictive computational framework for direct reprogramming between human cell types , 2016, Nature Genetics.

[95]  A. del Sol,et al.  A general strategy for cellular reprogramming: The importance of transcription factor cross‐repression , 2013, Stem cells.

[96]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[97]  Samantha A. Morris,et al.  CellNet: Network Biology Applied to Stem Cell Engineering , 2014, Cell.

[98]  O. Elemento,et al.  Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons , 2012, Cell.

[99]  J. Rinn,et al.  lincRNAs act in the circuitry controlling pluripotency and differentiation , 2011, Nature.

[100]  Andrew P. Feinberg,et al.  Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells , 2011, Nature Biotechnology.