FACT-mediated maintenance of chromatin integrity during transcription is essential for viability of mammalian stem cells

Replication and transcription machineries access DNA through unwrapping it from histone core. Preservation of nucleosome structure during replicatio n is a focus of intensive research, while maintenance of nucleosomes during transcription is less studied. Histone chaperone FACT is involved in transcription elongation, although whether it opens nucleosomes for polymerase or protects core histones from loss during passage of polymerase is still unclear. We used conditional knockout model of Ssrp1 , subunit of FACT complex, to deplete FACT in mice and monitored consequences of FACT loss to establish the functional relevance of FACT in mammals. FACT loss was lethal for mice at all ages due to failure of hematopoietic and intestinal tissues. In these tissues, only the progenitors completely vanished upon FACT loss, while number of some other cell types were changed up and down. Using isolated stem cells of several tissues we showed that FACT loss was toxic only for stem cells, but not for cells which were differentiated in vitro . Chromatin accessibility in stem cells was increased genome wide upon FACT depletion in transcription dependentmanner. The most prominent response to the loss of chromatin integrity upon FACT depletion in cells was activation of interferon signaling, followed by accumulation of immune cells in sensitive organs. Thus, in undifferentiated mammalian cells FACT keeps chromatin stable during transcription elongation and this function of FACT is essential for viability of stem cells. ### Competing Interest Statement The authors have declared no competing interest.