Nucleation-dependent propagation of Polycomb modifications emerges during the Drosophila maternal to zygotic transition
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PROVIDER: PRJNA1273894 | ENA |
REPOSITORIES: ENA
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Project description:The manuscript associated with these datasets seeks to address the timing of acquisition of chromatin modifications associated with Polycomb group (PcG) function during the maternal-to-zygotic transition of Drosophila melanogaster. PcG modifications including mono- and tri-methylation of Histone H3 at Lysine 27 (H3K27me1, me3) and ubiquitylation of H2A at lysine 118 (H2Aub) were measured by ChIP-seq in precisely staged embryo collections spanning large scale zygotic genome activation (ZGA), over nuclear divisions NC13 and three timepoints in NC14 (NC14-early, -mid, and -late). Additionally, marks associated with active transcription, including mono- di- and tri-methylation of Histone H3 at Lysine 4 (H3K4me1, me2, me3), RNA Pol2 phosphorylated at serine 5 of the C-terminal domain heptapeptide repeats, and acetylation of Histone H3 at Lysine 27 (H3K27ac) were measured at NC14. We additionally measured genomic localization of the H3K27me3 methyltransferase, Enhancer of zeste (E(z)), and of three factors known to bind Polycomb Response Elements, Pho, Combgap, and GAGA-Factor (GAF), by generating GFP chimeras to these proteins using CRISPR/Cas9 and performing ChIP against the GFP tagged proteins. Data for these GFP-ChIP-seq localization experiments is from embryos collected during NC14. To test for the contribution of DNA binding factors to the establishment of PcG modifications, we additionally measured deposition of H3K27me3 in embryos where GAF was sequestered from nuclei using Jabba Trap (JT-GAF), and measured H3K27me3, H2Aub, E(z), and RNA Pol2 in embryos from zelda mutant germline clones staged at mid-NC14. Negative control ChIP-seq datasets are provided in the form of anti-GFP ChIP in wild-type embryos that express no GFP tagged protein.
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Project description:Histone modifications regulate gene expression and development. To address how they are reprogrammed in human early development, we investigated key histone marks in human oocytes and early embryos. Unlike that in mouse, the permissive mark H3K4me3 largely exhibits canonical patterns at promoters in human oocytes. After fertilization, pre-zygotic genome activation (ZGA) embryos acquire permissive chromatin and widespread H3K4me3 in CpG-rich regulatory regions. By contrast, the repressive mark H3K27me3 undergoes global depletion. CpG-rich regulatory regions then resolve to either active or repressed states upon ZGA, followed by subsequent restoration of H3K27me3 at developmental genes. Finally, through combining chromatin and transcriptome maps, we revealed transcription circuitry and asymmetric H3K27me3 patterning during early lineage specification. Collectively, our data unveil a priming phase connecting human parental-to-zygotic epigenetic transition.
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Project description:Alzheimer’s Disease (AD) is the most common form of dementia and a leading global cause of human mortality and morbidity. Amyloid plaques of the amyloid beta (Aß) peptide are a universal pathological hallmark of AD and rare mutations in Aß can cause familial forms of AD (fAD). However, hundreds of additional mutations in Aß of uncertain significance are likely to exist in the human population, making clinical interpretation of genetic variation a difficult challenge even in this short peptide. Here, we use deep mutagenesis to quantify the effects of all possible single nucleotide variants and thousands of double mutations on the ability of Aß to nucleate amyloid fibrils in vivo. This data provides the first comprehensive view of how mutations alter the nucleation of an amyloid, reveals a modular organisation of mutational effects in Aß, and demonstrates the importance of charge in preventing nucleation. Moreover, the in vivo nucleation data, unlike computational predictors, accurately discriminates the known dominant fAD mutations. These results illustrate how deep mutagenesis can be used to genetically validate assays as discovery platforms. They also further prioritize nucleation as the critical biochemical event to target in order to prevent and treat AD.
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Project description:Maternal-to-zygotic transition (MZT) is a conserved and fundamental process during which the maternal environment of oocyte transits to the zygotic genome driven expression program, and terminally differentiated oocyte and sperm are reprogrammed to totipotency. It is initiated by maternal mRNAs and proteins during the period of zygotic genome quiescence after fertilization, followed by a gradual switch to zygotic genome activation and accompanied by clearance of maternal RNAs and proteins. A key question for embryonic development is how MZT process is regulated. Here we used a low-input proteomic analysis to measure the proteomic dynamics during early development of mouse maternal-to-zygotic transition.
2023-03-27 | PXD041023 | Pride
Project description:Upon fertilization, maternal factors direct development in a transcriptionally silent embryo. At the maternal-to-zygotic transition (MZT), a universal step in animal development, unknown maternal factors trigger zygotic genome activation (ZGA). In zebrafish, ZGA is required for gastrulation and clearance of maternal mRNAs, which is achieved in part by the conserved microRNA miR-430. However, the precise factors that activate the zygotic program remain largely unknown. Here we show that Nanog, Pou5f1 and SoxB1 are required for genome activation in zebrafish. We identified several hundred genes directly activated by maternal factors, thus constituting the first wave of zygotic transcription in zebrafish. Ribosome profiling in the pre-MZT embryo revealed that nanog, sox19b and pou5f1 are the most highly translated transcription factor mRNAs. Combined loss of function for Nanog, SoxB1 and Pou5f1 resulted in developmental arrest prior to gastrulation, and a failure to activate >75% of zygotic genes. Furthermore, we found that Nanog binds the miR-430 locus and together with Pou5f1 and SoxB1 initiate miR-430 expression and activity. Our results demonstrate that maternal Nanog, Pou5f1 and SoxB1 are required to initiate the zygotic developmental program and in turn trigger the clearance of the maternal program by activating miR-430 expression. Wild type and loss-of-function total mRNA sequencing of embryonic transcriptomes pre- and post-MZT; ribosome profiling pre-MZT
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