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

      Sahni, Hemant; Ross, Susan; Barbarulo, Alessandro; Solanki, Anisha; Lau, Ching-In; Furmanski, Anna L.; Saldaña, José Ignacio; Ono, Masahiro; Hubank, Mike; Barenco, Martino; et al. (Impact Journals, 2015-09-20)
      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.