Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes

Abstract

During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

Loss of histone methyltransferase SETD1B in oogenesis results in the redistribution of genomic histone 3 lysine 4 trimethylation

“…Publicly available datasets were downloaded from Gene Expression Omnibus (GEO), including: H3K27me3 and H3K27ac ChIP-seq in GV oocytes, H3K4me3 ChIP-seq from d5 non-growing oocytes, d10 growing oocytes, d15 GV oocytes, d25 GV oocytes, Dnmt3 cDKO and Dnmt3 WT GV oocytes, and RNA-seq from Mll2 cKO and WT GV oocytes (GSE93941) ( 40 ), RNA-seq for GV oocytes (GSE70116) ( 46 ), RNA-seq from size-selected oocytes (GSE86297) ( 47 ), RNA-seq from Setd1b cKO and WT MII oocytes (GSE85360) ( 37 ), RNA-seq from Cxxc1 cKO and WT GV oocytes (GSE85019) ( 39 ), H3K4me3 ChIP-seq and bisulfite-seq from Cxxc1 cKO and WT GV oocytes (GSE159581) ( 48 ), and bisulfite-seq from d12 and d15 GV oocytes (GSE72784) ( 41 ). All raw data files were mapped and trimmed using the pipelines described above.…”

Analyzing the impact of CFP1 mutational landscape on epigenetic signaling

“…Intriguingly, the same authors demonstrated that in the absence of SETD1A/B in ESCs, H3K4me3 is maintained by MLL2, suggesting that these enzymes share some overlapping functions. The idea was further confirmed recently in mouse oocyte 48 …”

“…The idea was further confirmed recently in mouse oocyte. 48 While each enzyme associates with a set of shared regulatory subunits that include WD Repeat 5 (WDR5), Retinoblastoma Binding Protein 5 (RbBP5), Acute Small Homeotic 2 Long (ASH2L), and Dumpy-30 (DPY-30), SETD1A/B also binds to WDR82 and CFP1. Loss of CPS40 (CFP1 yeast homolog) in yeast cells triggers a global loss of H3K4me3 with H3K4me2/me1 levels remaining relatively the same.…”

Loss of histone methyltransferase SETD1B in oogenesis results in the redistribution of genomic histone 3 lysine 4 trimethylation

“…Therefore, we hypothesized that H3K4me3 these sets of promoters may have differing dependencies on H3K4 methyltransferases. To test this, we included publically available H3K4me3 ChIP-seq data for Cxxc1 cKO and Mll2 cKO GV oocytes (40,48). Globally, Setd1b cKO and Cxxc1 cKO GV oocytes show remarkably similar patterns of H3K4me3 (Supplementary Figure 4A, 4B, 4C), further supporting their co-dependence in the oocyte.…”

“…Publicly available datasets were downloaded from Gene Expression Omnibus (GEO), including: H3K27me3 and H3K27ac ChIP-seq in GV oocytes, H3K4me3 ChIP-seq from d5 non-growing oocytes, d10 growing oocytes, d15 GV oocytes, d25 GV oocytes, Dnmt3 cDKO and Dnmt3 WT GV oocytes, and RNA-seq from Mll2 cKO and WT GV oocytes (GSE93941) (40), RNA-seq for GV oocytes (GSE70116) (46), RNA-seq from size-selected oocytes (GSE86297) (47), RNA-seq from Setd1b cKO and WT MII oocytes (GSE85360) (37), RNA-seq from Cxxc1 cKO and WT GV oocytes (GSE85019) (39), H3K4me3 ChIP-seq and bisulphite-seq from Cxxc1 cKO and WT GV oocytes (GSE159581) (48), and bisulphite-seq from d12 and d15 GV oocytes (GSE72784) (41,42). All raw data files were mapped and trimmed using the pipelines described above.…”