Transcription factor FOXM1 specifies the loading of chromatin DNA to extracellular vesicles

Abstract

Extracellular vesicle DNAs (evDNAs) possess the important diagnostic value for multiple diseases and play roles for horizontally transferring genetic materials among cells. In this study, we have found that transcription factor FOXM1 can mediate the loading of certain chromatin genes or DNA fragments (named FOXM1-chDNAs) to extracellular vesicles (EVs). FOXM1 interacts with LC3 in nucleus and FOXM1-chDNAs (such as DUX4 gene and Telomere DNA) are specified by FOXM1 and translocated to cytoplasm. These DNAs are released to EVs through the process of an LC3-involved autophagosome-multivesicular body (MVB) transport. The roles of FOXM1 on loading FOXM1-chDNAs to EVs are further confirmed by DNA-FISH experiments, tracing the translocation of selected chromatin loci with the TetO/TetR-GFP method, and PCR analysis of the DNA samples from MVBs and EVs. Furthermore, disrupting the expression of FOXM1 or the process of autophagosome-MVB transport impairs the loading of FOXM1-chDNAs to EVs. This discovery suggests that transcription factor FOXM1 contributes the constitution of evDNAs from nuclear chromatin, providing the first example to explain how chromatin DNA fragments are specified and loaded to EVs. It also provide a foundation to further explore the roles of evDNAs in biological processes such as the horizontal gene transfer.