A genome wide transcriptional model of the complex response to pre-TCR signalling during thymocyte differentiation

Article


Sahni, Hemant, Susan, Ross, Barbarulo, Alessandro, Solanki, Anisha, Lau, Ching-In, Furmanski, Anna, Saldaña, J., Ono, Masahiro, Hubank, Mike, Barenco, Martino and Crompton, Tessa 2015. A genome wide transcriptional model of the complex response to pre-TCR signalling during thymocyte differentiation. Oncotarget. 6 (30), pp. 28646-28660.
AuthorsSahni, Hemant, Susan, Ross, Barbarulo, Alessandro, Solanki, Anisha, Lau, Ching-In, Furmanski, Anna, Saldaña, J., Ono, Masahiro, Hubank, Mike, Barenco, Martino and Crompton, Tessa
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.

Keywordspre-TCR; thymus; foetal thymic organ cultures; DP; genome wide transcriptional modelling; Immunology Section; Immune response; Immunity
JournalOncotarget
Journal citation6 (30), pp. 28646-28660
ISSN1949-2553
Year2015
PublisherImpact Journals
Publisher's version
License
CC BY
Supplemental file
License
CC BY
Supplemental file
License
CC BY
Digital Object Identifier (DOI)doi:10.18632/oncotarget.5796
Publication dates
Print22 Sep 2015
Publication process dates
Deposited31 Jan 2017
Accepted08 Sep 2015
FunderWellcome Trust
Medical Research Council (MRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
UCL Graduate School
Wellcome Trust
Medical Research Council
Biotechnology and Biological Sciences Research Council
University College London
Asthma UK
Istituto Pasteur-Fondazione Cenci Bolognetti
Great Ormond Street Hospital for Children
Copyright information© 2015 The authors.
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