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Genome-wide dissection of the Notch-induced molecular program in developing T cells

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T cells play a critical role in active cell-mediated immunity. EU researchers have delved into the role of the Notch biochemical pathway in T cell development.

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The Notch pathway regulates various cell fate decisions during differentiation in multicellular organisms. The fact that Notch commits precursors of T lymphocytes to the T lineage and controls further differentiation is well known. However, knowledge is scant on the role of Notch further down in the molecular journey to fully fledged T cell. The NOTCH IN THYMOCYTES (Genome-wide dissection of the Notch-induced molecular program in developing T cells) project developed appropriate tools to identify Notch targets in the process. ChIP-sequencing produced genome-wide maps of knock-in alleles of Notch1 and its DNA-binding cofactor Rbpj. RNA-sequencing identified Notch involvement in the programme. Finally, RNA interference techniques pinpointed the Notch targets. Some findings were unexpected and very significant in many cases. As opposed to the belief that Rbpj is constantly bound to DNA, the researchers found Notch-dependent Rbpj binding in the majority of the sites. They also found a group of short-lived Notch targets and many genes were transcriptional for myeloid and natural killer T cells. Concerning T cell receptors (TCRs) where it is known that signalling strength drops on pre-TCR expression, project findings suggest that this is a subset of Notch targets and no new targets emerge after this point. NOTCH IN THYMOCYTES research findings represent the first systematic characterisation of Notch-induced development of primary cells. The knowledge base can be applied to other primary cell types as well as treatment for cancer immunotherapies.


T cells, cell fate, NOTCH IN THYMOCYTES, genome-wide, Notch targets, T cell receptors

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