L(3)mbt safeguards tissue identity by maintaining transcriptional integrity at head-to-head genes

Maintenance of cellular identity is essential for development and homeostasis and problems in such control can have dire consequences such as organ malformation or cancer. At the molecular level, cell identity is determined by the coordinated activation and repression of defined sets of genes. The tumor suppressor L(3)mbt was shown to secure cellular identity in Drosophila larval brains by repressing germline specific genes, although the mechanisms remain elusive. Here we show that L(3)mbt safeguards the integrity of the somatic and germline tissues forming the Drosophila ovary. L(3)mbt mutation causes multiple developmental defects and simultaneous expression of original identity markers and new tissue-specific misexpression signatures. We demonstrate that the ovarian developmental defects are largely due to the ectopic expression of nanos, a key regulator of germline fate in the somatic cells of the ovary, rather than to the loss of cellular identity. Importantly, using genome-wide analysis we found that L(3)mbt exerts boundary activity between differentially regulated genes by binding to high occupancy insulator sites enriched at the borders of topological domains. Using nanos as an example, we propose that L(3)mbt maintains cell fate and specific gene expression programs by locally insulating repressed genes from closely apposed transcribed neighbors.