Histone titration against the genome sets the DNA-to-cytoplasm threshold for the Xenopus midblastula transition

Embryos depend on maternally deposited RNA until zygotic transcription activates. In many species, genome activation coincides with cell cycle lengthening and cellular motility, which collectively comprise the midblastula transition (MBT). A long-standing model is that MBT onset is controlled by titration of a maternally loaded inhibitor against exponentially increasing DNA. To identify MBT inhibitors, we developed an assay using Xenopus egg extract that recapitulates transcriptional activation only above a DNA-to-cytoplasm ratio similar to MBT embryos and identified histones H3 and H4 as inhibitors. Changing histone levels quantitatively shifts the DNA concentration required for transcription in vitro and alters the onset of both zygotic transcription and cell cycle lengthening in vivo. Our work strongly supports histones as a titrated MBT inhibitor.