56 / 2026-04-02 09:30:41

长程染色质互作调控细胞全能性

相分离,DUX,全能性,三维基因组,长程染色质互作

The totipotency program requires extensive epigenetic reprogramming; however, the spatiotemporal regulation of this process by master regulators remains poorly understood. In this study, we demonstrate that DUX, a pivotal transcription factor initiating totipotency, forms nuclear condensates through its intrinsically disordered region. These condensates function as molecular hubs that selectively recruit the zinc-finger protein ZFP352 in the absence of direct physical interaction, thereby activating endogenous retroviruses and 2-cell (2C)-specific genes. Disruption of this co-condensation-achieved via a point mutation in DUX or knockout of Zfp352-abrogates the transition from pluripotency to totipotency. Mechanistically, DUX-ZFP352 condensates enhance chromatin accessibility and promote the formation of broad H3K4me3 domains at totipotency-associated genes. These broad domains participate in super-long-range chromatin interactions (SLRIs) with MERVL retrotransposons throughout the genome and are involved in the release of RNA polymerase II pausing, thereby promoting transcriptional activation. Notably, deletion of a single broad H3K4me3 domain is sufficient to disrupt SLRIs and impair totipotency. Our findings reveal a phase separation-mediated mechanism through which DUX and ZFP352 co-condensation reconfigure the three-dimensional epigenome to enable transcriptional activation essential for totipotent cell fate.