Chromatin-linked determinants of zygotic genome activation

Abstract

The merging of the maternal and paternal genomes into a single pronucleus after fertilization is accompanied by a remarkable reconfiguration of chromatin in the newly formed zygote. The first stages of embryonic chromatin remodeling take place in the absence of ongoing transcription, during a species-specific developmental time-frame. Once post-fertilization chromatin states are organized, zygotic genome activation (ZGA) is initiated, and embryonic transcripts gradually take control of development. We review here transitions in chromatin modifications associated with the onset of ZGA, and the role of transcription factors and DNA motifs in the regulation of ZGA. We propose a model of sequential chromatin remodeling events preceding ZGA, leading to the onset of embryonic transcription.

Fig. 1

Marking of sperm chromatin by DNA methylation, post-translational histone modifications and histone variants. a–c DNA methylation and histone modification patterns detected on housekeeping and developmental gene promoters in zebrafish sperm. a H3K4me3 enrichment at the TSS of DNA hypomethylated genes involved in cellular homeostasis. b, c Promoters of developmentally regulated genes are also DNA hypomethylated and marked by H3K4me3 together with b H3K27me3, or c H3K27me3 and H3K36me3. d Multivalent marking of the hoxa locus by modified histones, histone variant and DNA (hypo)methylation in zebrafish sperm. These chromatin immunoprecipitation and array hybridization profiles depict occupancy in histone variant H2AFV (top track), and in the following histone modifications: H3K14ac (absent from the hoxa locus), H3K4me2, H3K4me3 (these three marks are transcriptionally permissive), H3K27me3 (transcriptionally repressive) and H3K36me3 (commonly associated with transcriptionally active genes in somatic cells). Note the overlapping domains marked by H3K4me3, H3K27me3, and H3K36me3. This domain is depleted of DNA methylation (bottom track, beige). Panel d is reproduced and modified from Ref. [18] with permission

Fig. 2

Epigenetic pre-patterning of developmental gene expression by histone modifications in zebrafish embryos. a Prior to ZGA, developmentally important genes are marked by trimethylated H3K4, H3K9, and/or H3K27 in the promoter region. These genes are transcriptionally inactive during this developmental period. b At the time of ZGA, activated genes (right) lose any repressive mark they might have acquired prior to ZGA and become enriched in H3K36me3 and RNAPII downstream of the TSS, while H3K4me3 tends to extend towards the coding region. A number of genes marked by H3K4me3 (with or without any other modification) pre-ZGA also remain transcriptionally inactive at the time of ZGA, and are only activated later in development (left). These genes retain or acquire various combinations of repressive modifications, such as H3K27me3 alone (i), H3K27me3 and H3K9me3 (ii), H3K9me3 alone (iii), or lose all marks altogether, including H3K4me3 (iv)

Fig. 3

Unifying model of sequential chromatin remodeling events preceding ZGA during early development. (1) Pioneer transcription factors (TF) can recognize a DNA sequence motif (green mark) and interfere with linker histone H1 (black). (2) DNA-bound pioneer TFs recruit chromatin remodeling complexes (CRC) that (3) remodel surrounding nucleosomes. This includes a repositioning of nucleosomes, post-translational modifications of histones, and leads to exposure of the transcription start site of the target gene (TSS, red mark). DNA methylation states on the promoters of developmentally regulated genes do not significantly change during the pre-ZGA to ZGA transition; these promoters are largely unmethylated, enabling a transcriptionally permissive state. (4) This remodeling is permissive for recruitment of the RNAPII complex, and transcription initiation at the time of ZGA. Dashed line represents a developmental time interval between two chromatin states