Abstract
Vertebrate embryos achieve developmental competency during zygotic genome activation (ZGA) by establishing chromatin states that silence yet poise developmental genes for subsequent lineage-specific activation. Here, we reveal the order of chromatin states in establishing developmental gene poising in preZGA zebrafish embryos. Poising is established at promoters and enhancers that initially contain open/permissive chromatin with 'Placeholder' nucleosomes (bearing H2A.Z, H3K4me1, and H3K27ac), and DNA hypomethylation. Silencing is initiated by the recruitment of polycomb repressive complex 1 (PRC1), and H2Aub1 deposition by catalytic Rnf2 during preZGA and ZGA stages. During postZGA, H2Aub1 enables Aebp2-containing PRC2 recruitment and H3K27me3 deposition. Notably, preventing H2Aub1 (via Rnf2 inhibition) eliminates recruitment of Aebp2-PRC2 and H3K27me3, and elicits transcriptional upregulation of certain developmental genes during ZGA. However, upregulation is independent of H3K27me3 - establishing H2Aub1 as the critical silencing modification at ZGA. Taken together, we reveal the logic and mechanism for establishing poised/silent developmental genes in early vertebrate embryos.
Highlights
Vertebrate embryos initiate embryonic/zygotic transcription, termed zygotic genome activation (ZGA), and must distinguish active housekeeping genes from developmental genes, which must be temporarily silenced, but kept available for future activation (Chan et al, 2019; Lindeman et al, 2011; Murphy et al, 2018; Potok et al, 2013; Vastenhouw et al, 2010)
As H3K9me[3] and H3K27me[3] are very low or absent at ZGA in zebrafish, it remains unknown how developmental gene silencing occurs at ZGA within an apparently permissive chromatin landscape, and how subsequent H3K27me[3] is established at developmental genes during postZGA stages. 55 We addressed these issues further in zebrafish, which conduct full ZGA at the tenth synchronous 56 cell cycle of cleavage stage (~3.5 hours post fertilization, ~2000 cells)(Schulz et al, 2019)
We address the central issues regarding how developmental genes bearing Placeholder nucleosomes and H3K4me[3] are transcriptionally silenced during preZGA and ZGA stages in the absence of H3K27me[3], and how subsequent H3K27me[3] is focally established during postZGA (Figure 1 - figure supplement 1A). 72 73 Results H2Aub[1] is Present in PreZGA Zebrafish Embryo Chromatin First, we sought a repressive histone modification that might explain how developmental genes are silenced at ZGA
Summary
Vertebrate embryos achieve developmental competency during zygotic genome activation (ZGA) by establishing chromatin states that silence yet poise developmental genes for subsequent lineage-specific activation. We reveal the order of chromatin states in establishing developmental gene poising in preZGA zebrafish embryos. Silencing is initiated by the recruitment of Polycomb Repressive Complex 1 (PRC1), and H2Aub[1] deposition by catalytic Rnf[2] during preZGA and ZGA stages. During postZGA, H2Aub[1] enables Aebp2-containing PRC2 recruitment and H3K27me[3] deposition. Preventing H2Aub[1] (via Rnf[2] inhibition) eliminates recruitment of Aebp2-PRC2 and H3K27me[3], and elicits transcriptional upregulation of certain developmental genes during ZGA. 33 Impact Statement: De novo polycomb domains are formed in zebrafish early embryos by focal histone H2Aub[1] deposition by Rnf2-PRC1 – which imposes transcription silencing – followed by subsequent recruitment of Aebp2-PRC2 and H3K27me[3] deposition. We reveal the logic and mechanism for establishing poised/silent developmental genes in early vertebrate embryos. 33 Impact Statement: De novo polycomb domains are formed in zebrafish early embryos by focal histone H2Aub[1] deposition by Rnf2-PRC1 – which imposes transcription silencing – followed by subsequent recruitment of Aebp2-PRC2 and H3K27me[3] deposition. 39
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