Embryo development requires histone acetylation by Nejire during the maternal-to-zygotic transition
Authors: Audrey Marsh 1; George Hunt 2; Tyler Gibson 1; Elizabeth Larson 1; Katherine Hullin 1; Mattias Mannervik 2; Melissa Harrison 1
Affiliations: 1) Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI; 2) Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden
Keywords: j. epigenetics; d. histone variants and modifications
The sperm and egg are differentiated cell types, individually specialized for the purpose of fertilization. After merging to form the diploid genome, the new embryo must remove signatures in the parental genomes to reprogram to a totipotent state. Reprogramming is essential for the embryo to give rise to all the cell types of the adult organism. This reprogramming process occurs during a period called the maternal-to-zygotic transition (MZT). Initially transcriptionally quiescent, the zygotic genome is gradually activated by maternally encoded factors loaded into the oocyte prior to fertilization. Activation of the genome is controlled by a specialized set of transcription factors called pioneer factors, defined by their unique ability to bind and increase chromatin accessibility. In Drosophila melanogaster, the pioneer factor Zelda (ZLD) is an essential activator of zygotic transcription. Prior to ZLD-mediated genome activation, chromatin is largely comprised of nucleosomes devoid of post-translational modifications. Intriguingly, ZLD-bound sites are enriched with active histone acetylation marks, suggesting that a histone acetyltransferase (HAT) is functioning with ZLD to induce transcription. We showed that during the MZT Nejire (NEJ), the Drosophila homologue of the HAT family p300/CBP, bound to thousands of genomic loci that are also occupied by ZLD and that expression of ZLD in tissue culture resulted in increased acetylation at ZLD-bound loci. In the early embryo, ZLD knock down resulted in decreased acetylation and NEJ recruitment at shared sites. Together these data suggest ZLD mediates activation of the zygotic genome, at least in part, by recruiting NEJ to acetylate histones. To test whether NEJ-mediated acetylation during the MZT is required for development, we used the CRY2 optogenetic system to specifically inactivate NEJ during the period of widespread zygotic genome activation. Embryos treated with blue light through the MZT failed to hatch as compared to sibling controls left in the dark, indicating that NEJ is necessary during this early time in development. Our findings suggest a model in which pioneer factors are first to prime the genome for activation by recruiting histone acetyltransferases to cis-regulatory regions and that this is required for genome activation. Ongoing work is investigating the role of NEJ in activating the zygotic genome and establishing the mechanistic relationship between NEJ and the pioneer factor ZLD.