title: A genome wide transcriptional model of the complex response to pre-TCR signalling during thymocyte differentiation.
abstract: Developing thymocytes require pre-TCR signalling to differentiate from CD4-CD8- double negative to CD4+CD8+ double positive cell. Here we followed the transcriptional response to pre-TCR signalling in a synchronised population of differentiating double negative thymocytes. This time series analysis revealed a complex transcriptional response, in which thousands of genes were up and down-regulated before changes in cell surface phenotype were detected. Genome-wide measurement of RNA degradation of individual genes showed great heterogeneity in the rate of degradation between different genes. We therefore used time course expression and degradation data and a genome wide transcriptional modelling (GWTM) strategy to model the transcriptional response of genes up-regulated on pre-TCR signal transduction. This analysis revealed five major temporally distinct transcriptional activities that up regulate transcription through time, whereas down-regulation of expression occurred in three waves. Our model thus placed known regulators in a temporal perspective, and in addition identified novel candidate regulators of thymocyte differentiation.
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Hemant
authors.initials: H
authors.lastname: Sahni
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Ross
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barbarulo
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Anisha
authors.initials: A
authors.lastname: Solanki
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Ching-In
authors.initials: CI
authors.lastname: Lau
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Furmanski
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Saldaña
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Martino
authors.initials: M
authors.lastname: Barenco
authors.affiliation: Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Tessa
authors.initials: T
authors.lastname: Crompton
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016000:Cluster Analysis; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011498:Protein Precursors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D005819:Genetic Markers; D018398:Homeodomain Proteins; D011498:Protein Precursors; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C064658:RAG-1 protein; D012313:RNA
keywords: DP; Immune response; Immunity; Immunology Section; foetal thymic organ cultures; genome wide transcriptional modelling; pre-TCR; thymus