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. 2019 Apr 1;33(7-8):382-387.
doi: 10.1101/gad.323105.118. Epub 2019 Feb 26.

Maternal-biased H3K27me3 correlates with paternal-specific gene expression in the human morula

Wenhao Zhang #  1   2   3 , Zhiyuan Chen #  1   2   3 , Qiangzong Yin  1   2   3 , Dan Zhang  4   5   6 , Catherine Racowsky  4   5 , Yi Zhang  1   2   3   7   8
Affiliations

Maternal-biased H3K27me3 correlates with paternal-specific gene expression in the human morula

Wenhao Zhang et al. Genes Dev. .

Abstract

Genomic imprinting is an epigenetic mechanism by which genes are expressed in a parental origin-dependent manner. We recently discovered that, like DNA methylation, oocyte-inherited H3K27me3 can also serve as an imprinting mark in mouse preimplantation embryos. In this study, we found H3K27me3 is strongly biased toward the maternal allele with some associated with DNA methylation-independent paternally expressed genes (PEGs) in human morulae. The H3K27me3 domains largely overlap with DNA partially methylated domains (PMDs) and occupy developmental gene promoters. Thus, our study not only reveals the H3K27me3 landscape but also establishes a correlation between maternal-biased H3K27me3 and PEGs in human morulae.

Keywords: DNA methylation; allele-specific gene expression; genomic imprinting; human morulae; maternal-biased H3K27me3.

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Figures

Figure 1.
Figure 1.
H3K27me3 is enriched at developmental gene promoters in the human morula. (A) A schematic summary of the data sets generated in this study. H3K27me3 CUT&RUN was performed using pooled morulae collected from couple 1 (C1; n = 7) and couple 2 (C2; n = 8). Three replicates for single morula RNA-seq were performed for each couple. (B) Heat map showing gene expression levels and H3K27me3 enrichment at the corresponding gene bodies in human morulae. RPKM values are Z-score normalized and log2-transform normalized for CUT&RUN and RNA-seq, respectively. (C) A genome browser view showing H3K27me3 enrichment at HOXA and HOXD clusters, PAX6, and SOX3 in both morula and human embryonic stem cells (hESCs). (D) Heat map showing enrichment of H3K27me3 at promoters (transcription start site ± 2.5 kb) in morulae (two replicates) and hESCs. RPKM was subject to Z-score normalization.
Figure 2.
Figure 2.
H3K27me3 tends to overlap with DNA PMDs and is biased toward the maternal allele in the human morula. (A) A representative genome browser view showing H3K27me3 signals and DNA methylation in morula (two replicates) and H3K27me3 distribution in hESCs. (B) Heat maps showing the H3K27me3 signals and DNA methylation levels (5mC/C) surrounding PMDs in morula (upstream and downstream region = 5 × length of PMD). (C) Venn diagram showing overlaps between H3K27me3 domains and PMDs in morula. Random regions within the same chromatin and same length for each H3K27me3 domain were used as controls. (D) Plot showing the distribution of paternal/total reads ratio at SNPs identified from morula H3K27me3 CUT&RUN data by corroborating WGS data of couple 2 cumulus cells. The x-axis represents the ratio of paternal/total reads. The y-axis represents the frequency of corresponding paternal/total reads ratio in the x-axis. (E) Plot showing distribution of paternal reads/total reads ratio at SNPs identified from morula H3K27me3 CUT&RUN data by corroborating WES data of couple 1 or couple 2 cumulus cells. The x-axis represents the ratio of paternal reads/total reads. The y-axis represents the frequency of corresponding paternal/total reads ratio in the x-axis.
Figure 3.
Figure 3.
A subset of paternally expressed genes (PEGs) harbor germline differentially methylated regions (DMRs). (A) Heat map showing PEGs identified in this study. Each column represents one morula; a total of three morulae were analyzed for each couple. PEGs with oocyte hyper-DMR within 10 kb of the genes were considered as DMR-related (top panel). The remaining was considered as DMR unrelated (bottom panel). (B) Genome browser view showing examples of PEGs containing oocyte hyper-DMRs at promoter regions. DNA methylation in oocyte, sperm, and morula is shown.
Figure 4.
Figure 4.
Putative H3K27m3 associated PEGs and proposed model for mechanisms underlying paternal-biased expression. (A) A genome browser view showing H3K27me3 enrichment in morula and DNA methylation levels in oocyte, sperm, and morula at FAM101A locus. Red square represents the SNP identified from H3K27me3 CUT&RUN data. (B) Schematic model showing paternal allelic gene expression can be regulated by either allelic DNA methylation or allelic H3K27me3 in human morulae.
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