The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations

Abstract

Epidemiological research suggests that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean (discovery n = 47; replication n = 21) and obese (n = 22) males to analyse tissue covariation of DNA methylation, and identify obesity-associated methylomic signatures. We found that DNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). At the majority of these sites, DNA methylation appears to be influenced by genetic variation. Obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity was not associated with altered covariation patterns or accelerated epigenetic ageing in the two tissues. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P = 8.95 × 10 −8 ; 2% DNA methylation difference) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n = 5,917), spermatozoa displayed differential DNA methylation across pathways enriched in transcriptional regulation. Overall, human sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. We observed that obesity was only nominally associated with differential DNA methylation in PLOS GENETICS

Human methylome variation across Infinium 450K data on the Gene Expression Omnibus

“…While most probes mapped to open seas in liver (1014 probes), nasal (1100), adipose (1280) and sperm (1063), greater fractions of open sea probes mapped to genes in liver (70% of open sea probes), nasal (74%) and adipose (71%) than in sperm (52%, Figure 4C ). This observed sparsity of CpG island regions and enrichment of open sea, intergenic and gene body regions among CpG probes with tissue-specific DNAm was recently corroborated in an independent study comparing DNAm in matched sperm and blood samples directly ( 30 ). This corroboration was especially striking because the discovery set samples in ( 30 ) were processed on the newer EPIC/HM850K rather than the HM450K platform.…”

“…This observed sparsity of CpG island regions and enrichment of open sea, intergenic and gene body regions among CpG probes with tissue-specific DNAm was recently corroborated in an independent study comparing DNAm in matched sperm and blood samples directly ( 30 ). This corroboration was especially striking because the discovery set samples in ( 30 ) were processed on the newer EPIC/HM850K rather than the HM450K platform.…”

“…Finally, we characterized autosomal DNAm variation in 7484 samples from seven non-cancer tissue types. This analysis complements recent independent efforts to quantify tissue-specific DNAm patterns ( 30 ) and showcases several of the relatively rare sample types we compiled from GEO (e.g. sperm, adipose and nasal).…”

“…In 2013, two studies independently compiled DNAm array samples from GEO and elsewhere, analyzing epigenetic age across tissues and diseases ( 5 ), and investigating cross-study normalization ( 28 ). More recent cross-study analyses include ( 29 ) from 2018, which evaluated metadata and sample quality across 8327 DNAm array samples, and ( 30 ) from 2020, which validated sperm-specific DNAm patterns using 6288 samples.…”

Epigenetics of Male Infertility: The Role of DNA Methylation

“…Similarly, one investigation indicated that parental diet can modulate the methylation levels of several genes, including liver-specific genes involved in cholesterol/lipid metabolism, whereas no effect of paternal diet on sperm DNA methylation was found in other studies (Carone et al, 2010;Rando and Simmons, 2015;Shea et al, 2015;Whitelaw, 2015). Similarly, parental pre-conceptional obesity could potentially impact on the establishment of imprinting marks during embryogenesis (Soubry et al, 2015;Ou et al, 2019;Åsenius et al, 2020b;Keyhan et al, 2021). Changes in methylation in two imprinted genes, PLAGL1 and MEG3, have been detected in umbilical cord blood leukocytes in a group of newborns from obese mothers, making a link between maternal overnutrition and the impairment of imprinting marks in the offspring (Soubry et al, 2015).…”