SOMATIC LINE-1

LINE-1 ACTIVITY IN SOMATIC STEM CELLS: IMPACT AND GENOMIC MOSAICISM

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 Obiettivo del progetto (Objective)

'45% of the human genome is made of repeated DNA, and some types can be mobilized within the genome (mobile DNA). LINE-1 or L1 is the only autonomous active mobile DNA within the human genome, with 500.000 copies per haploid genome (~17% of the genome). Overall, L1 is responsible for ~30% of our genome. Due to its activity and number in the genome, the impact that L1 has and have on the genome is notable. L1 mobility can result in several human diseases (due to insertions within genes) and can also participate in gene creation. L1 mobility is an active process in the human population, and we have recently demonstrated that human embryonic stem cells (hESCs) express L1 and can accumulate new copies of L1. As a result, some of these new copies will be transmitted to newborn individuals. Recently, it has been demonstrated that L1 is active in several somatic adult cell types. These are by definition cell types that will not disperse new L1 copies in the population. As a consequence, these results are a paradigm for the notion of L1 as a piece of “selfish DNA”, which is in the genome solely by its ability to replicate within the genome. In the present application, we will determine the level of expression and activity of L1 elements in several somatic stem cell types (neuronal, mesenchymals, and hematopoietic) in order to inspect the impact and mosaicism generated by L1 in somatic human tissues. The determination of the somatic impact of LINE-1 will shed light in several biological processes: from its role in the Central Nervous System, to its implication in several human diseases (is LINE-1 involved in the progression of human diseases as cancer?). Furthermore, its study will allow the design of therapeutic approaches in order to control its activity in somatic tissues. It is worth mentioning that the somatic activity of LINE-1 could be involved in several human diseases.'

Introduzione (Teaser)

EU-funded research is uncovering the workings of a jumping gene that appears to be highly active in the human genome. The findings of the Somatic Line-1 project are set to shed new light on the involvement of the jumping gene in human disease.

Descrizione progetto (Article)

The focus of the project is a mobile stretch of deoxyribonucleic acid (DNA) called 'Long interspersed element 1', or Line-1, or even simply L1. This jumping gene is able to copy and paste itself across the genome, and it is so prolific that it is responsible for a third of the human genome. When L1 lands in the middle of a gene, it can have consequences on our health; diseases such as cancer and haemophilia have been attributed to mutations caused by L1. At the same time, many genes have incorporated L1 elements into their regulatory systems.

Among other things, Somatic Line-1's investigations have revealed that L1 is active in neuronal stem cells (NSCs) which have the potential to become different kinds of nerve cell.

The researchers have also found that there are more copies of L1 jumping around in our brain cells than in other tissues taken from the same donor. This suggests that the genome of our brain is not fixed, although further research is needed to determine the biological significance of this finding.

The project partners are now studying whether L1 activity is a characteristic of somatic stem cells in general, or if it is restricted to NSCs.

Looking to the future, the project is expected to contribute to our understanding of the workings of L1 and its impacts on human health. Bearing in mind L1's possible involvement in certain diseases, the findings could even lead to the development of drugs to control its activity.