SUMOylation of Linker Histone H1 Drives Chromatin Condensation and Restriction of Embryonic Cell Fate Identity [SMART-Seq]

The fidelity of the early embryonic program is underlined by tight regulation of the chromatin. Yet, our understanding of how the chromatin is organized to prohibit the reversal of the developmental program remains limited. Specifically, the totipotency to pluripotency transition marks one of the most dramatic events to the chromatin, yet the nature of histone changes and regulation underlying this process are only partly characterized. Here we show that linker histone H1 is post-translationally modulated by SUMO2/3, which facilitates its fixation onto ultra-condensed heterochromatin in embryonic stem cells (ESCs). Upon SUMOylation depletion, the chromatin becomes de-compacted and H1 is evicted, leading to totipotency reactivation. Further, we show that H1 and SUMO2/3 jointly mediate the repression of totipotent elements. Lastly, we demonstrate that preventing SUMOylation on H1 abrogates its ability to repress totipotency in ESCs. Collectively, our findings unravel a critical role for SUMOylation of H1 in mediating chromatin repression and desolation of the totipotent identity. RNA-seq was performed to measure changes in mRNA expression between UBC9-inhibited and DMSO-control morula mouse embryos. The selected embryos in this experiment were morphologically matched.