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Investigating the involvement of lincRNAs in aging of haematopoietic stem cells and in haematological malignancies

Final Report Summary - LINCAGE (Investigating the involvement of lincRNAs in aging of haematopoietic stem cells and in haematological malignancies)

Changes in epigenetic state are now recognized as an important factor implicated in both normal ageing and in age-associated disease. In recent years, a new class of molecules known as long non-coding RNAs (lncRNAs) has emerged as an important regulator of chromatin structure. lncRNAs are RNA molecules of >200 nucleotides which have no significant coding potential. Many of these molecules impact upon chromatin structure by acting as scaffolds to guide chromatin-modifying proteins to their genomic targets. At present, the contribution of lncRNAs to the chromatin changes observed in normal ageing and in age-associated disease has not been investigated.

One of the prominent changes occurring with age are alterations in the hematopoietic system, which contribute significantly to the decline in health of the elderly, by impacting on the ability of the immune system to protect against infectious agents and to respond to vaccination. These changes also contribute to the increased incidence of haematological malignancy. The objectives of the lincAge project were to investigate the contribution of lncRNAs and epigenetic changes to the decline of HSC function which is observed with normal ageing as well as in the aetiology of age-related haematological malignancy.

With the work performed in the lincAge project, progress has been made towards identifying molecules and epigenetic events which drive these changes in the haematological system. We have used both candidate approaches as well as mining of existing databases to identify and functionally characterize lncRNAs potentially implicated both in normal B-lymphoid differentiation, and in the loss of B cell potential which is observed with age and in an important age-associated B cell malignancy, multiple myeloma (MM). We have also characterized an important epigenetic pathway arising from a depleted expression of the histone methyltransferase SUV39H1, which contributes to the loss of B-lymphoid potential observed in haematopoietic stem cells with age and have partially rescued this phenotype in HSC from elderly individuals.

The molecules identified in this study have the potential to translate into clinical benefit both as biomarkers for disease or the “health status” of the immune system in the elderly, but also they represent potential targets for the design of novel therapeutic approaches to treat disease and to reverse the age-associated changes in the haematological system.