Histone variant H2A.Z regulates zygotic genome activation

Abstract

During embryogenesis, the genome shifts from transcriptionally quiescent to extensively active in a process known as Zygotic Genome Activation (ZGA). In Drosophila, the pioneer factor Zelda is known to be essential for the progression of development; still, it regulates the activation of only a small subset of genes at ZGA. However, thousands of genes do not require Zelda, suggesting that other mechanisms exist. By conducting GRO-seq, HiC and ChIP-seq in Drosophila embryos, we demonstrate that up to 65% of zygotically activated genes are enriched for the histone variant H2A.Z. H2A.Z enrichment precedes ZGA and RNA Polymerase II loading onto chromatin. In vivo knockdown of maternally contributed Domino, a histone chaperone and ATPase, reduces H2A.Z deposition at transcription start sites, causes global downregulation of housekeeping genes at ZGA, and compromises the establishment of the 3D chromatin structure. We infer that H2A.Z is essential for the de novo establishment of transcriptional programs during ZGA via chromatin reorganization.

Hierarchical Accumulation of Histone Variant H2A.Z Regulates Transcriptional States and Histone Modifications in Early Mammalian Embryos

“…These observations indicate that ZGA occurs coordinately with lineage commitment in lower animal embryos, whereas these two biological processes are relatively separate in mammals. Considering that H2A.Z accumulates before ZGA in Drosophila and zebrafish embryos, [ 42 , 43 ] but accumulates at the ZGA stage in mammalian embryos, we speculate that H2A.Z plays a distinct role in future gene expression between mammals and lower animals. It will be interesting to characterize the TFs and chromatin remodelers orchestrating ZGA and lineage commitment in different species.…”

The Role of the Histone Variant H2A.Z in Metazoan Development

“…In Drosophila and zebrafish, H2A.Z has been shown to be directly involved ( Figure 1 ). In Drosophila , H2A.Z is deposited at a subset of promoters before the induction of ZGA and recruitment of RNA pol II [ 41 ]. Experimental depletion of chromatin-bound H2A.Z leads to a reduction in RNA pol II occupancy and transcription of H2A.Z-bound genes, and defects in ZGA.…”

“…Experimental depletion of chromatin-bound H2A.Z leads to a reduction in RNA pol II occupancy and transcription of H2A.Z-bound genes, and defects in ZGA. H2A.Z-positive genes are enriched for housekeeping genes, which suggests that H2A.Z is important for the activation of genes that control basic cellular processes during ZGA [ 41 ]. In zebrafish, H2A.Z is thought to prevent DNA methylation, which represses transcription, and to protect the genome from incorrect methylation [ 37 , 42 , 46 ].…”

“…In Drosophila , the knockdown of maternal Domino, an SRCAP homolog, also causes a reduction in H2A.Z at TSSs and impairs the expression of housekeeping genes at ZGA. Notably, the deposition of H2A.Z precedes ZGA and, therefore, Domino is essential for the de-novo establishment of ZGA transcriptional programs [ 41 ].…”

“…The right panel shows the developmental processes that H2A.Z has been found to play a role in and depicts when during mouse development these processes occur. * Note that while this figure depicts mouse development, a direct role of H2A.Z in zygotic genome activation has only been shown in Drosophila and zebrafish to date [ 41 , 42 ].…”