Resetting epigenetic memory by reprogramming of histone modifications in mammals
Ontology highlight
ABSTRACT: Polycomb group proteins and the related histone modification H3K27me3 can maintain the silencing of key developmental regulators and provide cellular memory. However, how such epigenetic state is reprogrammed and inherited between generations is poorly understood. Using an ultra-sensitive approach STAR ChIP-seq, we investigated H3K27me3 across 14 developmental stages along mouse gametogenesis and early development. Interestingly, highly pervasive H3K27me3 was found in regions depleted of transcription and DNA methylation in oocytes. Unexpectedly, we observed extensive loss of promoter H3K27me3 at Hox and other developmental genes upon fertilization. This is accompanied by global erasure of sperm H3K27me3 but inheritance of distal H3K27me3 from oocytes. The resulting allele-specific H3K27me3 patterns persist to blastocysts before being converted to canonical forms in postimplantation embryos, where both the H3K4me3/H3K27me3 bivalent promoter marks are restored at developmental genes. Together, these data revealed widespread resetting of epigenetic memory and striking plasticity of epigenome during gametogenesis and early development.
Project description:Epigenetic resetting in the mammalian germ line entailsacute DNA demethylation, which lays the foundation for gametogenesis, totipotency,and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genesand transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCsexhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signaturesat most genesand TEsand the acquisition of a neutral or paused epigenetic state without transcriptional activation.Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such asevolutionarily young TEsand some developmental genes, which require H3K9me3 and H3K27me3, respectively, forefficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presentsan exemplary balanced system relying on local maintenance of heterochromatic featuresand a lack of inductive cues.
Project description:Epigenetic resetting in the mammalian germ line entailsacute DNA demethylation, which lays the foundation for gametogenesis, totipotency,and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genesand transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCsexhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signaturesat most genesand TEsand the acquisition of a neutral or paused epigenetic state without transcriptional activation.Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such asevolutionarily young TEsand some developmental genes, which require H3K9me3 and H3K27me3, respectively, forefficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presentsan exemplary balanced system relying on local maintenance of heterochromatic featuresand a lack of inductive cues.
Project description:Epigenetic resetting in the mammalian germ line entailsacute DNA demethylation, which lays the foundation for gametogenesis, totipotency,and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genesand transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCsexhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signaturesat most genesand TEsand the acquisition of a neutral or paused epigenetic state without transcriptional activation.Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such asevolutionarily young TEsand some developmental genes, which require H3K9me3 and H3K27me3, respectively, forefficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presentsan exemplary balanced system relying on local maintenance of heterochromatic featuresand a lack of inductive cues.
Project description:Epigenetic resetting in the mammalian germ line entailsacute DNA demethylation, which lays the foundation for gametogenesis, totipotency,and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genesand transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCsexhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signaturesat most genesand TEsand the acquisition of a neutral or paused epigenetic state without transcriptional activation.Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such asevolutionarily young TEsand some developmental genes, which require H3K9me3 and H3K27me3, respectively, forefficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presentsan exemplary balanced system relying on local maintenance of heterochromatic featuresand a lack of inductive cues.
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.
Project description:Replication disrupts chromatin organization. Thus, rapid resetting of nucleosome positioning is essential to maintain faithful gene expression. The initial step of this reconfiguration occurs at Nucleosome-Depleted Regions (NDRs). While studies have elucidated the role of Transcription Factors (TFs) and Chromatin Remodelers (CRs) in vitro or in maintaining NDRs in vivo, none has addressed their in vivo function shortly after replication. Through purification of nascent chromatin coupled with yeast genetics, we dissected the choreography of events governing the proper positioning of the -1/+1 nucleosomes flanking promoter NDRs. Our findings reveal that CRs are the primary contributors of -1/+1 repositioning post-replication, with RSC acting upstream of INO80. Surprisingly, while Reb1 and Abf1 TFs are not essential for NDR resetting, they are required for NDR maintenance via the promotion of H3 acetylations. Taken together, we propose a two-step model for NDR resetting in S. cerevisiae: first, CRs alone reset promoter NDRs after replication, while a combination of TFs and CRs is required for subsequent maintenance.
Project description:During angiosperm male gametogenesis, microspores divide to produce a vegetative cell (VC) and a male germline (MG), each with a distinct cell fate. How the MG cell/VC fate is determined remains largely unknown. Here, we report that the VC-targeted H3K27me3 erasure resulted in VC fate transition towards a gamete destination. Multi-omics and cytologic analysis reveal that H3K27me3 is essential for VC fate commitment and contributes to suppress the MG cell fate initiation in VC, whereas MG cells require H3K27me3 reprograming for the gamete cell fate. This work suggests that the MG cell/VC fate is epigenetically regulated. The dimorphic H3K27 methylation acts as a core switch to determine their distinct cell fates and ensure the functional specification of both VC and MG for pollen fertility. This work also provides direct evidences for the proposal that VC maintains the default developmental program of microspore, whereas MG requires reprogramming.
Project description:During angiosperm male gametogenesis, microspores divide to produce a vegetative cell (VC) and a male germline (MG), each with a distinct cell fate. How the MG cell/VC fate is determined remains largely unknown. Here, we report that the VC-targeted H3K27me3 erasure resulted in VC fate transition towards a gamete destination. Multi-omics and cytologic analysis reveal that H3K27me3 is essential for VC fate commitment and contributes to suppress the MG cell fate initiation in VC, whereas MG cells require H3K27me3 reprograming for the gamete cell fate. This work suggests that the MG cell/VC fate is epigenetically regulated. The dimorphic H3K27 methylation acts as a core switch to determine their distinct cell fates and ensure the functional specification of both VC and MG for pollen fertility. This work also provides direct evidences for the proposal that VC maintains the default developmental program of microspore, whereas MG requires reprogramming.
Project description:During angiosperm male gametogenesis, microspores divide to produce a vegetative cell (VC) and a male germline (MG), each with a distinct cell fate. How the MG cell/VC fate is determined remains largely unknown. Here, we report that the VC-targeted H3K27me3 erasure resulted in VC fate transition towards a gamete destination. Multi-omics and cytologic analysis reveal that H3K27me3 is essential for VC fate commitment and contributes to suppress the MG cell fate initiation in VC, whereas MG cells require H3K27me3 reprograming for the gamete cell fate. This work suggests that the MG cell/VC fate is epigenetically regulated. The dimorphic H3K27 methylation acts as a core switch to determine their distinct cell fates and ensure the functional specification of both VC and MG for pollen fertility. This work also provides direct evidences for the proposal that VC maintains the default developmental program of microspore, whereas MG requires reprogramming.