Oncotarget

Research Papers: Immunology:

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

Hemant Sahni, Susan Ross, Alessandro Barbarulo, Anisha Solanki, Ching-In Lau, Anna Furmanski, José Ignacio Saldaña, Masahiro Ono, Mike Hubank, Martino Barenco and Tessa Crompton _

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Oncotarget. 2015; 6:28646-28660. https://doi.org/10.18632/oncotarget.5796

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Abstract

Hemant Sahni1, Susan Ross1, Alessandro Barbarulo1, Anisha Solanki1, Ching-In Lau1, Anna Furmanski1, José Ignacio Saldaña1, Masahiro Ono1, Mike Hubank1, Martino Barenco1,* and Tessa Crompton1,*

1 Institute of Child Health, University College London, London WC1N 1EH, UK

* These authors are co-senior authors and contributed equally to this work

Correspondence to:

Tessa Cromp­ton, email:

Keywords: pre-TCR, thymus, foetal thymic organ cultures, DP, genome wide transcriptional modelling, Immunology Section, Immune response, Immunity

Received: July 07, 2015 Accepted: September 08, 2015 Published: September 22, 2015

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.


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