Epigenetic priming by Dppa2/4 in pluripotency facilitates multi-lineage commitment
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ABSTRACT:
PROVIDER: PRJNA560249 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11396200_1.fastq.gz | Fastqsanger.gz | |||
| SRR11396200_2.fastq.gz | Fastqsanger.gz | |||
| SRR11396201.fastq.gz | Fastqsanger.gz | |||
| SRR11396202.fastq.gz | Fastqsanger.gz | |||
| SRR11396203.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic priming factors establish a permissive epigenetic landscape which is not required until a later developmental or physiological time point, temporally uncoupling the presence of these factors with their phenotypic effects. One classic example of epigenetic priming is in the context of bivalent chromatin, found in pluripotent stem cells and early embryos at key developmental gene promoters marked by both activating-associated H3K4me3 and repressive-associated H3K27me3 histone modifications. It is currently unknown how these bivalent domains are targeted, or precisely how they impact on lineage commitment. Here we show that the small heterodimerising non-enzymatic DNA binding proteins Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) act as epigenetic priming factors to establish bivalency at a subset of developmental genes. Dppa2/4 localise to the +1 nucleosome position of bivalent genes and while they are not required for pluripotency in embryonic stem cells (ESCs), double knockout cells fail to exit pluripotency and to differentiate efficiently, with delays in upregulating bivalently marked lineage genes. Proteomics reveal that Dppa2/4 interact on chromatin with members of the COMPASS and Polycomb complexes important for H3K4me3 and H3K27me3 deposition, respectively. Epigenetic profiling reveals a striking loss of H3K4me3, H3K27me3, and their associated enzymatic machinery at a significant subset of bivalent promoters in Dppa2/4 mutants, in addition to loss of H2A.Z and chromatin accessibility. In wild-type ESCs, these “Dppa2/4-dependent” bivalent promoters are characterised by low H3K4me3 enrichment and breadth, near-absent expression levels and initiating but not elongating RNA polymerase. Notably, Dppa2/4-dependent promoters are less evolutionarily conserved suggesting that they lack additional safeguard measures to maintain bivalency at these genes in the absence of Dppa2/4. Concomitantly with the loss of bivalency, Dppa2/4-dependent bivalent promoters gain DNA methylation and consequently are no longer able to be effectively activated upon ESC differentiation, leading to defects in cell fate acquisition. Our findings reveal a targeting principle for bivalency to developmental gene promoters poising them for future lineage specific gene activation.
2020-06-23 | GSE135841 | GEO
Project description:Epigenetic priming factors establish a permissive epigenetic landscape which is not required until a later developmental or physiological time point, temporally uncoupling the presence of these factors with their phenotypic effects. One classic example of epigenetic priming is in the context of bivalent chromatin, found in pluripotent stem cells and early embryos at key developmental gene promoters marked by both activating-associated H3K4me3 and repressive-associated H3K27me3 histone modifications. It is currently unknown how these bivalent domains are targeted, or precisely how they impact on lineage commitment. Here we show that the small heterodimerising non-enzymatic DNA binding proteins Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) act as epigenetic priming factors to establish bivalency at a subset of developmental genes. Dppa2/4 localise to the +1 nucleosome position of bivalent genes and while they are not required for pluripotency in embryonic stem cells (ESCs), double knockout cells fail to exit pluripotency and to differentiate efficiently, with delays in upregulating bivalently marked lineage genes. Proteomics reveal that Dppa2/4 interact on chromatin with members of the COMPASS and Polycomb complexes important for H3K4me3 and H3K27me3 deposition, respectively. Epigenetic profiling reveals a striking loss of H3K4me3, H3K27me3, and their associated enzymatic machinery at a significant subset of bivalent promoters in Dppa2/4 mutants, in addition to loss of H2A.Z and chromatin accessibility. In wild-type ESCs, these “Dppa2/4-dependent” bivalent promoters are characterised by low H3K4me3 enrichment and breadth, near-absent expression levels and initiating but not elongating RNA polymerase. Notably, Dppa2/4-dependent promoters are less evolutionarily conserved suggesting that they lack additional safeguard measures to maintain bivalency at these genes in the absence of Dppa2/4. Concomitantly with the loss of bivalency, Dppa2/4-dependent bivalent promoters gain DNA methylation and consequently are no longer able to be effectively activated upon ESC differentiation, leading to defects in cell fate acquisition. Our findings reveal a targeting principle for bivalency to developmental gene promoters poising them for future lineage specific gene activation.
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Project description:Pluripotent Embryonic Stem Cells (ESCs) can be captured in vitro in different states, ranging from unrestricted ‘naïve’ to more developmentally constrained ‘primed’ pluripotency. Complexes involved in epigenetic regulation and key transcription factors have been shown to be involved in specifying these distinct states. In this study, we use proteomic profiling of the chromatin landscape in naive pluripotent ESCs, Epistem cells (EpiSCs) and early differentiated ESCs to survey the chromatin in naïve and primed pluripotency and during differentiation. We provide a comprehensive overview of epigenetic complexes situated on the chromatin and identify proteins associated with the maintenance and loss of pluripotency. The findings presented here indicate major compositional alterations of epigenetic complexes starting from ESC priming onwards. Our results contribute to the understanding of ESC differentiation and provide a framework for future studies of lineage commitment of ESCs.
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Project description:As somatic cells are converted to iPSCs, their chromatin undergoes wide-ranging rearrangements that affect the ratio of euchromatin-to-heterochromatin, DNA methylation patterns and the regulation of enhancers and promoters. The molecular machinery underlying this process remains largely unknown. Here, we show that Dppa2 and Dppa4, two thus far poorly characterized mES-specific factors, play a key role in resetting the epigenome to a pluripotent configuration. They function as a heterodimer, are induced in late reprogramming intermediates, and are required for reprogramming. When overexpressed with OSKM factors, Dppa2/4 yield reprogramming efficiencies exceeding 75% of the starting culture and accelerate reprogramming kinetics, generating iPSCs in as little as 4 days. When chromatinbound, Dppa2/4 initiate global chromatin decompaction via the DNA damage response pathway, which subsequently activates mES promoters and enhancers and enables an efficient progression to pluripotency. Our work provides critical insights into how the epigenome is remodeled during cell fate transitions.
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Project description:As somatic cells are converted to iPSCs, their chromatin undergoes wide-ranging rearrangements that affect the ratio of euchromatin-to-heterochromatin, DNA methylation patterns and the regulation of enhancers and promoters. The molecular machinery underlying this process remains largely unknown. Here, we show that Dppa2 and Dppa4, two thus far poorly characterized mES-specific factors, play a key role in resetting the epigenome to a pluripotent configuration. They function as a heterodimer, are induced in late reprogramming intermediates, and are required for reprogramming. When overexpressed with OSKM factors, Dppa2/4 yield reprogramming efficiencies exceeding 75% of the starting culture and accelerate reprogramming kinetics, generating iPSCs in as little as 4 days. When chromatinbound, Dppa2/4 initiate global chromatin decompaction via the DNA damage response pathway, which subsequently activates mES promoters and enhancers and enables an efficient progression to pluripotency. Our work provides critical insights into how the epigenome is remodeled during cell fate transitions.
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Project description:Zygotic Genome Activation (ZGA) represents the initiation of transcription following fertilization. Despite its importance in shifting developmental control from primarily maternal stores in the oocyte to the embryo proper, we know little of the molecular events that initiate ZGA in vivo. Recent in vitro studies in mouse embryonic stem cells (ESCs) have revealed Developmental Pluripotency Associated 2 and 4 (Dppa2/4) as key regulators of ZGA-associated transcription. However, their roles in initiating ZGA in vivo remain unexplored. We reveal Dppa2/4 proteins are present in the nucleus at all stages of preimplantation development and associate with mitotic chromatin. We generated single and double maternal knockout mouse models to deplete maternal stores of Dppa2/4. Importantly, while fertile, Dppa2/4 maternal knockout mice had reduced litter sizes, indicating decreased offspring survival. Immunofluorescence and transcriptome analyses of 2-cell embryos revealed while ZGA took place there were subtle defects in embryos lacking maternal Dppa2/4. Strikingly, heterozygous offspring that inherited the null allele maternally had higher preweaning lethality than those that inherited the null allele paternally. Together our results show that while Dppa2/4 are dispensable for ZGA transcription, maternal stores have an important role in offspring survival, potentially via epigenetic priming of developmental genes.
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