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Tet enzymes are essential for early embryogenesis and completion of embryonic genome activation

ABSTRACT: Mammalian development begins in transcriptional silence followed by a period of widespread activation of thousands of genes. DNA methylation reprogramming is integral to embryogenesis and linked to Tet enzymes, but their function in early development is not well understood. Here, we generate combined deficiencies of all three Tet enzymes in mouse oocytes using a morpholino-guided knockdown approach and study the impact of acute Tet enzyme deficiencies on preimplantation development. Tet1-3 deficient embryos arrest at the 2-cell stage with the most severe phenotype linked to Tet2. Individual Tet enzymes display non-redundant roles in the consecutive oxidation of 5-methylcytosine to 5-carboxylcytosine. Gene expression analysis uncovers that Tet enzymes are required for completion of embryonic genome activation (EGA) and fine-tuned expression of transposable elements and chimeric transcripts. Whole-genome bisulfite sequencing reveals minor changes of global DNA methylation in Tet deficient 2-cell embryos, suggesting an important role of non-catalytic functions of Tet enzymes in early embryogenesis. Our results demonstrate that Tet enzymes are key components of the clock that regulates the timing and extent of EGA in mammalian embryos.

SUBMITTER: Julia Arand

PROVIDER: S-SCDT-EMBOR-2021-53968V1 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BACKGROUND: In all Metazoa, transcription is inactive during the first mitotic cycles after fertilisation. In Drosophila melanogaster, Zygotic Genome Activation (ZGA) occurs in two waves, starting respectively at mitotic cycles 8 (approximately 60 genes) and 14 (over a thousand genes). The regulatory mechanisms underlying these drastic transcriptional changes remain largely unknown. RESULTS: We developed an original gene clustering method based on discretized transition profiles, and applied it to datasets from three landmark early embryonic transcriptome studies. We identified 417 genes significantly up-regulated during ZGA. De novo?motif discovery returned nine motifs over-represented in their non-coding sequences (upstream, introns, UTR), three of which correspond to previously known transcription factors: Zelda, Tramtrack and Trithorax-like (Trl). The nine discovered motifs were combined to scan ZGA-associated regions and predict about 1300 putative cis-regulatory modules. The fact that Trl is known to act as chromatin remodelling factor suggests that epigenetic regulation might play an important role in zygotic genome activation. We thus systematically compared the locations of predicted CRMs with ChIP-seq profiles for various transcription factors, 38 epigenetic marks from ModENCODE, and DNAse1 accessibility profiles. This analysis highlighted a strong and specific enrichment of predicted ZGA-associated CRMs for Zelda, CBP, Trl binding sites, as well as for histone marks associated with active enhancers (H3K4me1) and for open chromatin regions. CONCLUSION: Based on the results of our computational analyses, we suggest a temporal model explaining the onset of zygotic genome activation by the combined action of transcription factors and epigenetic signals. Although this study is mainly based on the analysis of publicly available transcriptome and ChiP-seq datasets, the resulting model suggests novel mechanisms that underly the coordinated activation of several hundreds genes at a precise time point during embryonic development.

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Tet enzymes are essential for early embryogenesis and completion of embryonic genome activation

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