Affiliation: Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Stem Cells and Tissue Homeostasis Group, Paris, France.
Keywords: d. intestinal stem cells; i. dosage compensation
Aneuploidy, the loss or gain of chromosomes, is the most prevalent genetic hallmark of cancer. However, in a normal context, it is difficult to assess its frequency and its impact as aneuploid cells are often eliminated. It is not known whether chromosome gain or loss happens in healthy stem cells, whether this changes during aging, or how stem cells cope with it. Here, we use the Drosophila intestinal stem cell model to explore these questions. Our previous data from whole genome sequencing in aged female Drosophila midguts have revealed a loss of an entire X chromosome (monosomy), suggesting that stem cells in healthy tissue can undergo aneuploidy. We have developed a genetic system to study this further, based on the loss-of-heterozygosity (LOH) of an X-linked tumor suppressor gene, whereby loss of the wild-type X chromosome results in neoplastic growth. Using a specific marker, we confirmed that loss of an X chromosome occurs frequently (1 in 800 stem cells). How do these cells survive and compensate for the sudden loss of an entire chromosome? We believe that part of the answer lies with buffering by the dosage compensation (DC) pathway, which in male cells deposits H4K16ac on the single X and increases its transcription. We show that DC becomes activated in female monosomic cells, indicating for the first time that a X chromosome counting mechanism still exists in adult cells. We are now testing whether DC is required in monosomic cells for neoplasia formation and effectively buffers the loss of one X. Our data suggest that another factor promoting the survival and fitness of aneuploid cells could be loss tumor suppressor activity. Indeed, X chromosome monosomy is more frequent when a tumor suppressor is inactivated than in a wild-type context. This suggests that the inactivation of tumor suppressor genes could foster an environment where aneuploid cells can survive and thrive. Together, our work shows that monosomy happens frequently in healthy stem cells, is an important mechanism of LOH and can be viable, making it a driving force of tumorigenesis.