The endocycle is a cell cycle variant that is composed of alternating G and S phases without mitosis. Repeated endocycles result in polyploidy and large cell size. Cells switch from mitotic cycles to endocycles (M-E switch) during the normal development of numerous organisms, including protozoa, insects, plants, and mammals. It is known that the endocycle oscillator is regulated by alternating activity of Cyclin E / CDK2 and APC/Ccdh1. Yet, the molecular mechanisms that remodel the mitotic cycle into the endocycle are mostly not understood. We previously analyzed the transcriptome of endocycling cells in the Drosophila larval salivary gland and fat body. This study revealed that endocycling cells have dampened expression of genes that are regulated by the E2F1 / Dp and Myb-MuvB (MMB a.k.a. dREAM) transcription factor complexes. It is well established that the MMB can act as either a transcriptional activator or repressor to regulate mitotic cell cycle progression in a variety of organisms, including humans. Many of the MMB-regulated genes that are required for mitotic entry / progression and cytokinesis were expressed at lower levels during fly endocycles. We are currently exploring whether remodeling of the MMB from a transcriptional activator to repressor promotes the M-E switch.
Genetic ablation of mitosis can create induced endocycling cells (iECs). For example, RNAi knockdown of Cyclin A or overexpression of the APC/C activating subunit Fzr (CDH1) both block mitosis and switch cells to an endocycle oscillator. These iECs represent an opportunity to investigate mechanisms of the M-E switch independent of developmental inputs. Our current results suggest that these iECs also have dampened expression of MMB-regulated genes. These results suggest that MMB activity is integrated with the master cell cycle control system, the mechanisms of which we are defining further. It has been shown that polyploid cells in several tissues of the mouse have a transcriptome signature similar to that which we described for fly endocycles. The insights into endocycle regulation revealed by our study, therefore, will likely be conserved across organisms including humans. Moreover, evidence suggests that some cancer cells inappropriately switch to endocycles, which may lead to genome instability and cancer progression. Therefore, this study also has broader impact for understanding the molecular circuitry of these cancer iECs.