Analyses of inter-individual variations of sperm DNA methylation and their potential implications in cattle

- Analyses of inter-individual variations of sperm DNA methylation and their potential implications in cattle.
- Background: DNA methylation has been shown to be involved in many biological processes, including X chromosome inactivation in females, paternal genomic imprinting, and others..
- Using a weighted correlation network analysis (WGCNA), we also detected a co-regulated module of HVMRs that was significantly associated with reproduction traits, and enriched for glycosyltransferase genes, which play critical roles in spermatogenesis and fertilization.
- Additionally, we identified 46 VMRs significantly associated with reproduction traits, nine of which were regulated by cis-SNPs, implying the possible intrinsic relationships among genomic variations, DNA methylation, and phenotypes.
- Conclusion: In summary, our results demonstrated associations of sperm DNA methylation with reproduction traits, highlighting the potential of epigenomic information in genomic improvement programs for cattle..
- DNA methylation in sperm has been shown to be involved in many biological pro- cesses, including X chromosome inactivation in females,.
- Some alterations of sperm DNA methylation may persist into the early em- bryo and thus influence the transcriptome and epigenome in somatic tissues [9, 10], leading to variation in pheno- types of offspring [11].
- 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0.
- Full list of author information is available at the end of the article.
- for understanding the relationships between sperm DNA methylation and complex traits in mammals, particularly in males..
- Variation of DNA methylation among individuals has been speculated to affect susceptibility to complex diseases and resistance to drug treatment in human [12–14].
- In addition, inter-individual methylation variations have been demonstrated to be associated with tissue- specific function and environmental adaptation [15]..
- While VMRs were studied in human and model organisms, to our knowledge, no studies have been published to investigate inter- individual variation of DNA methylation in cattle, particularly in sperm, which is of importance in dairy cattle due to the wide use of artificial insemination technology..
- Because adjacent CpG sites tend to show the coordinated methylation statuses due to the progressivity of the DNA methylation and/or demethylation enzymes (DNMT1, DNMT3A/B and TET proteins), these co-.
- Collectively, blocks with coordinately methyl- ated 5mC were likely to capture the epigenetic signatures associated with transcriptional regulation..
- A total of 1952 bovine MHBs were overlapped with those from human [23], and asso- ciated with 1701 human genes, while the cattle-specific MHBs were associated with 5832 genes.
- GO terms related to early embryonic development, while those associated with cattle-specific MHBs (CMHBs) were mainly enriched in the development of nervous system (FDR <.
- 1 Schematic overview of the current study.
- We associated the methylation levels of VMRs with 41 complex traits.
- Genes associated with hypo-CMRs generally had the highest expression, followed by genes associated with hyper- CMRs and genes associated with HVMRs (Fig.
- Func- tional annotation further revealed that genes associated with hypo-CMRs were engaged in basic cell-function, including transcription, DNA binding and nuclear chromatin (Add- itional file 1: Figure S3a), suggesting that these genes were mainly house-keeping genes.
- in motifs associated with hemopoietic development and al- ternative splicing, like MZF1 and CELF2.
- Methylation levels of the MHB were low in sperm but high in oocyte.
- This result indicates that genomic regions associated with.
- mean sperm DNA methylation of all methylation haplotype blocks (MHBs), and distribution of highly variable methylated regions (HVMRs), hypomethylated conserved regions (Hypo-CMRs) and hypermethylated conserved regions (Hyper-CMRs).
- b Average methylation levels of HVMR, Hypo-CMRs and Hyper-CMRs in 16 somatic tissues.
- c Average expression levels (FPKM value) of genes associated with HVMR, Hypo-CMRs and Hyper-CMRs in 91 tissues and cell types.
- Collect- ively, our data revealed distinct DNA methylation variation patterns in sperm might influence the transcriptional regula- tion and evolution..
- HVMRs were associated with QTLs of reproduction traits To explore the relationship between HVMRs in sperm and complex traits, we first examined the QTL regions of six categories of traits (n = 232) (Exterior, health, Meat, milk, production and reproduction traits) from the Cattle QTL database (https://www.animalgenome..
- While hyper-CMRs were highly associated with a range of complex traits such as milk production traits, non- return rate and calving ease (CE) (Fig.
- Elements in red dash box were two traits most significantly associated with module 1.
- Methylation levels of VMRs were transferred from β values to M values for association tests [37]..
- The most significant VMR associ- ated with DPR was within exon 2 of the ZFP36L1 gene.
- 0.83) between methylation levels of this VMR.
- e Expression levels (FPKM values) of four genes associated with significant VMRs across 91 bovine tissues.
- Another example was the suggestively significant VMR associated with GL, which is located ~ 5.9 kb downstream of the CRISP2 gene.
- We examined the transcriptome of 91 bovine tissues, and observed four genes associated with significant VMRs (CRISP2, HGF, EFHB and ARFGEF3) showing high expression pat- terns almost exclusively in sperm and testis (Fig.
- Examples of the trait-associated VMRs which were influenced by genetic variations.
- Out of the 46 VMRs, nine were associated with at least one cis-SNP (FDR <.
- rs109326022 is the most significant SNP associated with the VMR methy- lation level.
- Among the three genotypes, individuals with GG have the highest DNA methylation level but lowest PTA values for DPR and CCR, and those with TT have the lowest DNA methylation level but highest PTA values (Fig.
- On the other hand, a previous DNA methylation study identified ASPDH as a gene.
- 6 A trait-related variably methylated region (VMR) was associated with a SNP within 1 Mb distance.
- a UCSC browser of the VMR associated with CCR and DPR as well as the methylation QTL (meQTL) associated with the trait-related VMR (chr .
- PL and SCE were the most significant traits associated with the meQTL.
- c Methylation levels of the trait-related VMR in three genotypes of rs109326022.
- This cis-meQTL was most signifi- cantly associated with PL and SCE among all tested traits (Fig.
- To our knowledge, this is the first report to characterize the inter-individual variation of sperm DNA methylation and to explore their associations with complex traits in cattle.
- In our association studies, about half of the signifi- cant/suggestively significant VMRs were within 10 kb of annotated genes (Fig.
- Besides ZFP36L1 and CRISP2 mentioned before, we detected the HGF gene, whose VMR was significantly associated with DPR..
- associated with DPR in BTA18 (Additional file 1: Figure S4).
- This was also supported by our previous study, which reported sperm DNA methylation alterations in this region were associated GL, sire.
- Therefore, the influence of the prominent QTL on fertil- ity traits could be a combination of both genetic and epi- genetic mechanisms..
- Our results indicated the sperm DNA methylation variation associates with reproduction traits in bulls, which were estimated based on the reproduction per- formance of their daughters, such as DPR, CCR, GL and PL.
- While DNA methylation erasure occurred after fertilization, in- duced transgenerational epimutations appear to be protected from it.
- Sperm DNA methylation and sperm RNA could both persist into embryo and even adult tissues, impacting the phenotypes of offspring.
- Another potential mech- anism is that the genetic factors, such as the genetic variants like SNPs associated with DNA methylation (meQTLs), are transmitted to offspring via sperm DNA.
- We have shown that the genetic effects on DNA methylation could not be dismissed, as about 20% of trait-associated VMRs were influenced by gen- etic variations.
- Another study demonstrated that 44% of the methylation variation was best explained by gen- etic factors [20].
- Therefore, al- though our study performed an initial exploration be- tween sperm DNA methylation and sire fertility traits, it will be interesting for future work to study the mechanisms how sire sperm epigenetic signatures may impact reproduction traits in female progenies..
- For example, comparing epigenetic information be- tween sire sperm and embryo could provide insights on retained DNA methylation marks..
- TssA are active promoters and are associated with developmentally important genes [56]..
- Also we used sperm as our target to analyze the correlation between DNA methylation and phenotypes.
- Therefore, in the near future it is urgent to design either PCR- or array-based high-throughput DNA methylation assays, for example, a low-density bovine methylation array covering important functional regions similar to the Infinium human methylation arrays.
- In summary, our study of sperm DNA methylation variation provides novel insights into the biological basis underlying complex traits in cattle,.
- We then compared the SD of the methylation levels of each MHB to the median SD using the chi-square test for variance.
- found the methylation levels of MHBs tend to be dy- namic among individuals.
- To increase the power of the association studies, we conducted two steps of quality control.
- Methylation levels of VMRs were transferred from β values to M values.
- (a) Functional enrichment of genes associated with Hypo CMRs.
- (c) Enrichment of human orthologous genes associated with HVMRs, Hypo CMRs and Hyper CMRs in tissue-specific genes.
- A trait-related VMR was associated with an SNP within 1 Mb distance.
- (a) The UCSC browser of the epigenetic markers associated with CCR and DPR as well as the methylation QTLs (meQTLs) associated with the trait- related VMR (chr .
- (c) Methylation levels of the trait-related VMR in two geno- types of rs41893756..
- Identified methylation haplotype blocks (MHBs) in sperm DNA methylation.
- Significant VMRs associated with bovine complex traits and the most significant meQTL within 1 Mb of these VMRs.
- in the writing of the manuscript.
- Holstein bulls were collected with approval of the US Department of Agriculture Agricultural Research Service Institutional Animal Care and Use Committee under Protocol 16 – 016.
- Aberrant sperm DNA methylation predicts male fertility status and embryo quality.
- DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos.
- Establishment and functions of DNA methylation in the germline.
- DNA methylation restrains transposons from adopting a chromatin signature permissive for meiotic recombination.
- Developmental origins of transgenerational sperm DNA methylation epimutations following ancestral DDT exposure.
- Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.
- Epigenome-wide association studies identify DNA methylation associated with kidney function.
- A survey of inter-individual variation in DNA methylation identifies environmentally responsive co-regulated networks of epigenetic variation in the human genome.
- Genome-wide DNA methylation map of human neutrophils reveals widespread inter-individual epigenetic variation.
- Exercise and inflammation-related epigenetic modifications: focus on DNA methylation..
- A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue.
- DNA methylation links intrauterine stress with abnormal nephrogenesis.
- Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns.
- Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies.
- Functional annotation of the cattle genome through systematic discovery and characterization of chromatin states and butyrate-induced variations.
- Genome variants associated with RNA splicing variations in bovine are extensively shared between tissues.
- Overlap between eQTL and QTL associated with production traits and fertility in dairy cattle..
- Sugar-coated sperm: unraveling the functions of the mammalian sperm glycocalyx.
- Temporal surge of glycosyltransferase activities in the genital tract of the hamster during the estrous cycle.
- Male fertility status is associated with DNA methylation signatures in sperm and transcriptomic profiles of bovine preimplantation embryos.
- Characterizing genetic and environmental influences on variable DNA methylation using monozygotic and dizygotic twins.
- Comparative whole genome DNA methylation profiling of cattle sperm and somatic tissues reveals striking hypomethylated patterns in sperm

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