Figure - available from: Nature Genetics
This content is subject to copyright. Terms and conditions apply.
![H2AK119ub1 dynamics and gene expression during the maternal-to-zygotic transition
a, Genome browser views of H2AK119ub1 and H3K27me3 dynamics at gene deserts. MII, MII oocyte. 1C, 1-cell. E2C, early 2-cell. L2C, late 2-cell. Mor, morula. Bl, blastocyst. Epi, E6.5 epiblast. b, c, Heatmaps showing the H2AK119ub1 and H3K27me3 enrichment at promoters (b) and gene bodies (c) in the maternal allele of the indicated samples. Genes with few SNP reads [RPKM(H2AK119ub1) < 1 in all samples] were filtered out from this analysis. The gene expression levels are shown in the right RNA-seq heatmap. The H3K27me3 ChIP-seq datasets are from¹⁸. The RNA-seq datasets are from¹⁶. d, Pie chart showing the proportion of putative H3K27me3-dependent imprinted genes²⁷ in Group A/B/C of the panel c. Genes with few SNP reads [RPKM(H2AK119ub1) < 1 in all samples] were filtered out from this analysis. The total number of genes in this pie chart is 62. e, Pie chart showing the proportion of typical Polycomb (PcG) target genes in Group A/B/C of the panel b. Genes with few SNP reads [RPKM(H2AK119ub1) < 1 in all samples] were filtered out from this analysis. The total number of genes in this pie chart is 1,405. f, Genome browser views of H2AK119ub1 and H3K27me3 dynamics at typical PcG targets. The genomic length of each view is indicated at the top. ESC, embryonic stem cells.](publication/350642236/figure/fig3/AS:1009464882774017@1617686591211/H2AK119ub1-dynamics-and-gene-expression-during-the-maternal-to-zygotic-transition-a.jpg)
H2AK119ub1 dynamics and gene expression during the maternal-to-zygotic transition a, Genome browser views of H2AK119ub1 and H3K27me3 dynamics at gene deserts. MII, MII oocyte. 1C, 1-cell. E2C, early 2-cell. L2C, late 2-cell. Mor, morula. Bl, blastocyst. Epi, E6.5 epiblast. b, c, Heatmaps showing the H2AK119ub1 and H3K27me3 enrichment at promoters (b) and gene bodies (c) in the maternal allele of the indicated samples. Genes with few SNP reads [RPKM(H2AK119ub1) < 1 in all samples] were filtered out from this analysis. The gene expression levels are shown in the right RNA-seq heatmap. The H3K27me3 ChIP-seq datasets are from¹⁸. The RNA-seq datasets are from¹⁶. d, Pie chart showing the proportion of putative H3K27me3-dependent imprinted genes²⁷ in Group A/B/C of the panel c. Genes with few SNP reads [RPKM(H2AK119ub1) < 1 in all samples] were filtered out from this analysis. The total number of genes in this pie chart is 62. e, Pie chart showing the proportion of typical Polycomb (PcG) target genes in Group A/B/C of the panel b. Genes with few SNP reads [RPKM(H2AK119ub1) < 1 in all samples] were filtered out from this analysis. The total number of genes in this pie chart is 1,405. f, Genome browser views of H2AK119ub1 and H3K27me3 dynamics at typical PcG targets. The genomic length of each view is indicated at the top. ESC, embryonic stem cells.
Source publication
Parental epigenomes are established during gametogenesis. While they are largely reset after fertilization, broad domains of Polycomb repressive complex 2 (PRC2)-mediated formation of lysine 27–trimethylated histone H3 (H3K27me3) are inherited from oocytes in mice. How maternal H3K27me3 is established and inherited by embryos remains elusive. Here,...
Citations
... Deficiency for Pcgf1, another component of vPRC1.1, indicated a role for this complex in defining H2AK119u1 and transcriptional states in oocytes 36 . Here, we study the role of Kdm2b and its paralog Kdm2a in regulating PRC1mediated gene repression and de novo DNAme acquisition during oogenesis and the impact of their loss-of-function on embryogenesis 34,28 . ...
... To understand the transcriptional regulatory function of KDM2A/KDM2B, we profiled RNA transcriptomes in single FGOs, from single and double mutants ( Figures S2A and S2B). Compared to ctrl oocytes, over 1400 genes were upregulated in Kdm2a KO Kdm2b KO In FGOs, H2AK119u1 and H3K27me3 were previously reported to co-occupy broad genomic regions, while dual marking by H2AK119u1 and H3K4me3 were shown to label promoters of expressed genes 36,37,21,38 . To derive the syntax of DNA sequence and chromatin configurations underlying the gene regulatory function of KDM2A/KDM2B proteins, we selected CGI and non-CGI promoter genes ( Figure S3C) and partitioned each gene group into eight clusters by k-means clustering, based on occupancy levels of H3K4me3 21 , H3K27me3 39 Figure 3G). ...
In mammalian somatic and male germline cells, genomes are extensively DNA methylated (DNAme). In oocytes, however, DNAme is largely limited to transcribed regions only. Regulatory CpG-island (CGI) sequences are also devoid of repressive DNAme in somatic and germ cells of both sexes. The mechanisms restricting de novo DNAme acquisition in developing oocytes, at CGIs and globally, and the relevance thereof for regulating zygotic gene expression and embryo development after fertilization are largely unknown. Here we show that the histone H3 lysine 36 dimethyl (H3K36me2) demethylases KDM2A and KDM2B prevent genome-wide accumulation of H3K36me2, thereby impeding global DNMT3A-catalyzed de novo DNAme, including at CGI gene promoters. By recruiting variant Polycomb Repressive Complex 1 (vPRC1), they further control H2A mono-ubiquitin deposition and vPRC1-dependent gene repression. Through genetic perturbations, we demonstrate that aberrant Dnmt3a -dependent DNAme established in Kdm2a/Kdm2b double mutant oocytes represses transcription from maternal loci in two-cell embryos. The lethality of Kdm2a/Kdm2b maternally deficient pre-implantation embryos is suppressed by Dnmt3a deficiency during oogenesis. Hence, KDM2A/KDM2B are essential for confining the oocyte DNA methylome, conferring competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient to erase aberrant DNAme from maternal chromatin, and that early development is vulnerable to gene dosage haplo-insufficiency effects.
HIGHLIGHTS
Demethylation of H3K36me2 by KDM2A and KDM2B prevents aberrant de novo DNA methylation in mouse oocytes.
Sequence composition and H3K4me3 modulate the probability for aberrant H3K36me2 and DNA methylation at CpG islands.
Aberrant oocyte DNA methylation is not reprogrammed in early embryos and suppresses maternal gene transcription.
Aberrant oocyte DNA methylation causes embryonic lethality during pre-implantation development.
GRAPHICAL SUMMARY
... Several studies point towards an epigenetic contribution of sperm for embryonic 38 development. First, in several species paternal exposure to various environmental 39 ...
... this sequence of events have been investigated in the mouse and zebrafish 330 embryos 19,20, 38 . In these embryos H2AK119ub1 is also required for the deposition of 331 ...
Deposition of H2AK119ub1 by the polycomb repressive complexe-1 plays a key role in the initiation of facultative heterochromatin formation in somatic cells. Here we evaluate the contribution of sperm derived H2AK119ub1 to embryo development. In Xenopus laevis we found that H2AK119ub1 is retained during spermiogenesis and into early embryonic development, highlighting its credential for a role in the transmission of epigenetic information from the sperm to the embryo. In vitro treatment of sperm with USP21, a H2AK119ub1 deubiquitylase, just prior to injection to egg, results in developmental defects associated with gene upregulation. Sperm H2AK119ub1 editing disrupts egg factor mediated paternal chromatin remodelling processes. It leads to post-replication accumulation of H2AK119ub1 on repeat element of the genome instead of CpG islands. This shift in post-replication H2AK119ub1 distribution triggered by sperm epigenome editing entails a loss of H2AK119ub1 from genes misregulated in embryos derived from USP21 treated sperm. We conclude that sperm derived H2AK119ub1 instructs egg factor mediated epigenetic remodelling of paternal chromatin and is required for embryonic development.
... The PRC can be classified into two types; PRC1 induces the ubiquitination of the lysine 119 residue on histone H2A [56], whereas PRC2 catalyzes the mono-, di-, and tri-methylation of the lysine 27 residue on histone H3 [57]. The connection between the H2A119ub and H3K27me3 histone modifications can be established through the recruitment of PRC1 to chromatin via the binding of the classic PRC1 component CBX protein to the histone mark H3K27me3 [58], and H2AK119ub1 can guides zygotic deposition of H3K27me3 in mouse early embryos [59]. It has been demonstrated in multiple experiments that HDACs participate in the process of histone modification that is involved in polycomb-protein-mediated silencing by interacting with EZH2, which is the main component of PRC2 [60][61][62][63]. ...
Background
Histone acetylation, which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a crucial role in the control of gene expression. HDAC inhibitors (HDACi) have shown potential in cancer therapy; however, the specific roles of HDACs in early embryos remain unclear. Moreover, although some pan-HDACi have been used to maintain cellular undifferentiated states in early embryos, the specific mechanisms underlying their effects remain unknown. Thus, there remains a significant knowledge gap regarding the application of selective HDACi in early embryos.
Results
To address this gap, we treated early embryos with two selective HDACi (MGCD0103 and T247). Subsequently, we collected and analyzed their transcriptome data at different developmental stages. Our findings unveiled a significant effect of HDACi treatment during the crucial 2-cell stage of zygotes, leading to a delay in embryonic development after T247 and an arrest at 2-cell stage after MGCD0103 administration. Furthermore, we elucidated the regulatory targets underlying this arrested embryonic development, which pinpointed the G2/M phase as the potential period of embryonic development arrest caused by MGCD0103. Moreover, our investigation provided a comprehensive profile of the biological processes that are affected by HDACi, with their main effects being predominantly localized in four aspects of zygotic gene activation (ZGA): RNA splicing, cell cycle regulation, autophagy, and transcription factor regulation. By exploring the transcriptional regulation and epigenetic features of the genes affected by HDACi, we made inferences regarding the potential main pathways via which HDACs affect gene expression in early embryos. Notably, Hdac7 exhibited a distinct response, highlighting its potential as a key player in early embryonic development.
Conclusions
Our study conducted a comprehensive analysis of the effects of HDACi on early embryonic development at the transcriptional level. The results demonstrated that HDACi significantly affected ZGA in embryos, elucidated the distinct actions of various selective HDACi, and identified specific biological pathways and mechanisms via which these inhibitors modulated early embryonic development.
... CUT&Tag was conceptualized as a more efficient alternative to ChIP-seq and the CUT&RUN method, successfully generating H3K27me3 profiles from as few as 60 human K562 cells [15]. Although CUT&Tag profiles have been obtained from > 1000 bovine blastomeres in a work by Zhou et al. [16], investigations on mouse blastomeres indicate that postponing the binding step using concanavalin-coated magnetic beads after antibody incubation can safeguard delicate blastomeres, yielding CUT&RUN profiles from as few as 100 blastomeres [17,18]. ...
Background
We previously reported a modification of the CUT&Tag method (NTU-CAT) that allows genome-wide histone modification analysis in individual preimplantation embryos. In the present study, NTU-CAT was further simplified by taking advantage of the Well-of-the-Well (WOW) system, which enables the processing of multiple embryos in a shorter time with less reagent and cell loss during the procedure (WOW-CUT&Tag, WOW-CAT).
Results
WOW-CAT allowed histone modification profiling from not only a single blastocyst but also from a portion of it. WOW-CAT generated similar H3K4me3 profiles as NTU-CAT, but they were closer to the profiles produced by chromatin immunoprecipitation-sequencing, such as a valley-like trend and relatively lower false positive rates, indicating that WOW-CAT may attenuate the bias of Tn5 transposase to cut open chromatin regions. Simultaneous WOW-CAT of two halves of single blastocysts was conducted to analyze two different histone modifications (H3K4me3 and H3K27ac) within the same embryo. Furthermore, trophectoderm cells were biopsied and subjected to WOW-CAT in anticipation of preimplantation diagnosis of histone modifications. WOW-CAT allowed the monitoring of epigenetic modifications in the main body of the embryo. For example, analysis of H3K4me3 modifications of XIST and DDX3Y in trophectoderm biopsies could be used to sex embryos in combination with quantitative PCR, but without the need for deep sequencing.
Conclusions
These results suggest the applicability of WOW-CAT for flexible epigenetic analysis of individual embryos in preimplantation epigenetic diagnosis.
... 12 In ESCs, the distinct PRC1 forms co-localize at the same targets, where they compensate for H2AK119ub1 deposition and repression. 13,14 Indeed, all knockout (KO) mouse models for the different PCGFs displayed developmental defects [15][16][17][18] but without phenocopying the early developmental block of RING1A/B KOs. 6 This highlights compensatory and specific functions that could not be identified in their molecular details. ...
... 22,25,26 Pcgf6 KO mice are viable and fertile, although they are born at sub-Mendelian ratios with developmental defects that are compatible with Polycomb functions. 17,27 These mice also displayed aberrant activation of germline gene expression, 17,18,28,29 without altering promoter CpG methylation. 30,31 PRC1.6 repressed germline genes prior to acquisition of DNA methylation, 18,30 and Pcgf6 KO mice displayed defects in sperm development that were linked to the direct control of germline transcription. ...
... 17,27 These mice also displayed aberrant activation of germline gene expression, 17,18,28,29 without altering promoter CpG methylation. 30,31 PRC1.6 repressed germline genes prior to acquisition of DNA methylation, 18,30 and Pcgf6 KO mice displayed defects in sperm development that were linked to the direct control of germline transcription. 17 This function is not shared with other forms of PRC1 and may not only involve RING1A/B activity. ...
... After fertilization, the allele carrying the mark is imprinted and its expression silenced, although there are far more complex forms of transregulation between imprinted regions and the coding regions they control (Cleaton et al., 2014;Sanli & Feil, 2015). In mammals, parental genomic imprinting involves DNA methylation at the majority of the c. 200 imprinted loci (Tucci et al., 2019) and imprints of a smaller number of paternally expressed loci result from the deposition in the oocyte of two histone posttranslational modifications by the Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2): ubiquitination of histone H2A (H2Aub) and trimethylation of lysine 27 on histone H3 (H3K27me3), respectively (Inoue et al., 2017;Chen & Zhang, 2020;Mei et al., 2021;Inoue, 2023). Flowering plants also display genomic imprinting, which results from an interplay between DNA methylation and H3K27me3 (Choi et al., 2002;Kinoshita et al., 2004;Gehring et al., 2006;Jullien et al., 2006a,b This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. ...
We are becoming aware of a growing number of organisms that do not express genetic information equally from both parents as a result of an epigenetic phenomenon called genomic imprinting. Recently, it was shown that the entire paternal genome is repressed during the diploid phase of the life cycle of the liverwort Marchantia polymorpha. The deposition of the repressive epigenetic mark H3K27me3 on the male pronucleus is responsible for the imprinted state, which is reset by the end of meiosis. Here, we put these recent reports in perspective of other forms of imprinting and discuss the potential mechanisms of imprinting in bryophytes and the causes of its evolution.
... Moreover, the H2AK119ub1 domains on maternal genome are more than that on paternal genome in zygotes. 106,110 H2AK119ub1 is removed in broad distal domains and progressively deposited at typical polycomb targets canonically after 1-cell stage, leading to a parental comparable distribution at the late 2-cell stage embryos. 106,110,111 Controversially, a recent study indicated that the H2AK119ub1 is largely diminished after meiotic resumption and nearly undetectable in MII oocytes, arguing that the maternal H2AK119ub1 in zygotes is newly established after fertilization. ...
... 106,110 H2AK119ub1 is removed in broad distal domains and progressively deposited at typical polycomb targets canonically after 1-cell stage, leading to a parental comparable distribution at the late 2-cell stage embryos. 106,110,111 Controversially, a recent study indicated that the H2AK119ub1 is largely diminished after meiotic resumption and nearly undetectable in MII oocytes, arguing that the maternal H2AK119ub1 in zygotes is newly established after fertilization. 112 Notably, the dynamic changes in levels and status of H3K27me3 and H2AK119ub1 during MZT might be critical for early embryo development. ...
... 89,109 H2AK119ub1 is co-established with H3K27me3 during oocyte growth, which is mediated by PRC1 and participates in transcriptional repression. 110,116 Oocyte-specific deletion of RING1A/1B, two core components of PRC1 components, causes absent of H2AK119ub1, aberrant transcription in oocytes, impaired ZGA, and developmental arrest at the 2-cell stage. 117 After meiotic resumption, Rong et al. found that the level of H2AK119ub1 is promptly declined genome-widely, and USP16 is indicated to be the major contributor to this meiotic-coupled H2AK119ub1 deubiquitination. ...
After fertilization, sperm and oocyte fused and gave rise to a zygote which is the beginning of a new life. Then the embryonic development is monitored and regulated precisely from the transition of oocyte to the embryo at the early stage of embryogenesis, and this process is termed maternal-to-zygotic transition (MZT). MZT involves two major events that are maternal components degradation and zygotic genome activation. The epigenetic reprogramming plays crucial roles in regulating the process of MZT and supervising the normal development of early development of embryos. In recent years, benefited from the rapid development of low-input epigenome profiling technologies, new epigenetic modifications are found to be reprogrammed dramatically and may play different roles during MZT whose dysregulation will cause an abnormal development of embryos even abortion at various stages. In this review, we summarized and discussed the important novel findings on epigenetic reprogramming and the underlying molecular mechanisms regulating MZT in mammalian embryos. Our work provided comprehensive and detailed references for the in deep understanding of epigenetic regulatory network in this key biological process and also shed light on the critical roles for epigenetic reprogramming on embryonic failure during artificial reproductive technology and nature fertilization.
... [23] This maternal Polycomb-dependent imprinting is initially established by PRC1-mediated H2AK119ub during oogenesis and then maintained as H3K27me3 during preimplantation development, thereby revealing the PRC1-dependent regulation of PRC2 activities. [24] Whereas maternal H3K27me3 is required for embryogenesis, it is dispensable for oogenesis. [25] In contrast, PRC1-mediated H2AK119ub is required for oogenesis; a deficiency in PRC1 function leads to massive gene derepression, developmental defects in oocytes, and subsequent one-cell arrest after fertilization. ...
... [26] Moreover, H2AK119ub and H3K27me3 undergo distinct reprogramming dynamics in early embryos. [24,27] These observations demonstrate a unique epigenome, including distinct patterns of DNA methylation and histone modifications, is formed during oocyte growth and undergoes extensive reprogramming during preimplantation development. The major remaining questions are how the epigenome in NGOs is established and maintained before these critical events and how it leads to epigenetic programming during oocyte growth. ...
The ovarian reserve defines female reproductive lifespan, which in humans spans decades. The ovarian reserve consists of oocytes residing in primordial follicles arrested in meiotic prophase I and is maintained independent of DNA replication and cell proliferation, thereby lacking stem cell-based maintenance. Largely unknown is how cellular states of the ovarian reserve are established and maintained for decades. Our recent study revealed that a distinct chromatin state is established during ovarian reserve formation in mice, uncovering a novel window of epigenetic programming in female germline development. We showed that an epigenetic regulator, Polycomb Repressive Complex 1 (PRC1), establishes a repressive chromatin state in perinatal mouse oocytes that is essential for prophase I-arrested oocytes to form the ovarian reserve. Here we discuss the biological roles and mechanisms underlying epigenetic programming in ovarian reserve formation, highlighting current knowledge gaps and emerging research areas in female reproductive biology.
... In mice, H3K4me3 becomes distributed over broad domains at non-transcribed genic and intergenic regions through the action of MLL2 and contributes to transcriptional silencing (Dahl et al. 2016;Zhang et al. 2016;Hanna et al. 2018). H3K27me3 and H2AK119Ub also expand to intergenic regions Chen et al. 2021;Mei et al. 2021). Together, these post translational modification patterns contribute to a novel form of maternal non-canonical imprint regulating embryonic growth (Inoue et al. 2017;Hanna and Kelsey 2017;Mei et al. 2021). ...
... H3K27me3 and H2AK119Ub also expand to intergenic regions Chen et al. 2021;Mei et al. 2021). Together, these post translational modification patterns contribute to a novel form of maternal non-canonical imprint regulating embryonic growth (Inoue et al. 2017;Hanna and Kelsey 2017;Mei et al. 2021). Yet, thesenon-canonical imprints seem to diverge between species as human oocytes are devoid of such contribute to a novel form of maternal non-canonical patterns of (Lu et al. 2021). ...
During mammalian reproduction, germ cell chromatin packaging is key to prepare parental genomes for fertilization and to initiate embryonic development. While chromatin modifications such as DNA methylation and histone post-translational modifications are well known to carry regulatory information, histone variants have received less attention in this context. Histone variants alter the stability, structure and function of nucleosomes and, as such, contribute to chromatin organization in germ cells. Here, we review histone variants expression dynamics during the production of male and female germ cells, and what is currently known about their parent-of-origin effects during reproduction. Finally, we discuss the apparent conundrum behind these important functions and their recent evolutionary diversification.
... Meanwhile, the oocyte exhibits a specific histone modification landscape, with broad domains of the repressive Polycomb Repressive Complex 2 (PRC2)-deposited histone 3 lysine 27 trimethylation (H3K27me3; see Glossary, Box 1) (Zheng et al., 2016). Interestingly, a subset of these parental chromatin differences persists throughout preimplantation development (Mei et al., 2021;Chen et al., 2021;Lismer et al., 2020) (Fig. 1C). Thus, like DNA methylation, histone modifications deposited in gametes and maintained during development may regulate gene expression in a parent-of-origin manner. ...
Classical genomic imprints are regulated by parent-specific DNA methylation levels inherited from the gametes in mammals. Imprints control gene expression in a parent-of-origin manner and are essential for development. A distinct class of so-called 'non-canonical' imprints was recently discovered; these are seemingly regulated by histone methylation and govern parent-specific expression of developmentally important genes, most notably in the placenta. This new class of imprinted genes expands the repertoire of asymmetric parental contributions in mammalian embryogenesis, and raises new questions about the functionality of imprinted gene regulation in mammalian development. In this Spotlight, we summarize the latest findings regarding non-canonical imprinting, mainly from the mouse model, and discuss what we know about the conservation of this phenomenon and how it impacts mammalian development.
