A gene expression signature classifying telomerase and ALT immortalization II

A gene expression signature classifying telomerase and ALT immortalisation reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT Telomere length is maintained by 2 known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The molecular mechanisms regulating the ALT phenotype are poorly understood and it is unknown how the decision of which pathway to activate is made at the cellular level. We have shown previously that active repression of telomerase gene expression by chromatin remodelling of the promoters is one mechanism of regulation, however other genes and signalling networks are likely to be required to regulate telomerase and maintain the ALT phenotype. Using gene expression profiling we have uncovered a signature of 1305 genes to distinguish telomerase positive and ALT cell lines. By combining this with gene expression profiles of liposarcoma tissue samples we refined this signature to 297 genes significantly associated with telomere maintenance mechanism. Network analysis of known direct interactions between genes within this signature revealed a regulatory signalling network consistent with a model of hTERT repression in ALT cell lines and liposarcomas. This network expands on our existing knowledge of hTERT regulation and provides a platform to understand differential regulation of hTERT in different tumour types and normal tissues. In addition we show evidence to suggest a novel mesenchymal stem cell origin for ALT immortalisation in cell lines and mesenchymal tissues. Keywords: cell type comparison, gene expression Immortal cell lines, normal cell strains and hMSC samples were all performed in duplicate. Liposarcoma samples were run as single samples apart from S904R (Peritoneal_Liposarcoma_ALT_2) which was run in duplicate.