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


Autoři: Fredrika Åsenius aff001;  Tyler J. Gorrie-Stone aff002;  Ama Brew aff003;  Yasmin Panchbhaya aff004;  Elizabeth Williamson aff005;  Leonard C. Schalkwyk aff002;  Vardhman K. Rakyan aff003;  Michelle L. Holland aff006;  Sarah J. Marzi aff007;  David J. Williams aff001
Působiště autorů: UCL EGA Institute for Women’s Health, University College London, London, United Kingdom aff001;  School of Biological Sciences, University of Essex, Colchester, United Kingdom aff002;  The Blizard Institute, Queen Mary University of London, London, United Kingdom aff003;  UCL Genomics, Great Ormond Street Institute of Child Health, London, United Kingdom aff004;  Fertility & reproductive medicine laboratory, University College Hospital, London, United Kingdom aff005;  Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King’s College London, London, United Kingdom aff006;  UK Dementia Research Institute, Imperial College London, London, United Kingdom aff007;  Department of Brain Sciences, Imperial College London, London, United Kingdom aff008
Vyšlo v časopise: The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations. PLoS Genet 16(10): e32767. doi:10.1371/journal.pgen.1009035
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009035

Souhrn

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 sperm, and therefore suggest that spermatozoal DNA methylation is an unlikely mediator of intergenerational effects of metabolic traits.

Klíčová slova:

Blood – Body mass index – DNA methylation – DNA replication – Gene ontologies – Obesity – Single nucleotide polymorphisms – Sperm


Zdroje

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