ArticlebioRxiv : the preprint server for biology2026
FACT depletion results in a temporal cascade of chromatin disruption preceding transcriptional collapse in stem cells.
Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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6 authors.
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Abstract
The histone chaperone FACT is essential for chromatin organization and stem cell identity, yet the sequence of events through which FACT maintains chromatin integrity remains unclear. We generate a high-resolution temporal map of events leading to chromatin destabilization and cell identity loss in murine embryonic stem cells following dTAG-mediated depletion of FACT. Loss of FACT initiates a rapid cascade, with nucleosome phasing disruption and reduced H3K4me3 beginning within 10 minutes in a transcription-dependent manner. This architectural destabilization enables pluripotency transcription factors to ectopically occupy gene bodies. FACT loss results in RNA Polymerase II accumulation within 30 minutes and altered H3K36me3 deposition preceding a global transcriptional collapse at 2 hours of FACT depletion. FACT restoration fails to rescue these defects, demonstrating they are largely irreversible. Our findings define a temporal hierarchy in which FACT loss drives progressive deterioration of chromatin architecture, leading to transcriptional collapse in stem cells.
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