Developmental Biology & Stem CellsDNA Methylation and Hydroxymethylation

Battle of the Sexes: Autosomal DNA methylation tells us that men and women are more different than we thought

The genetic factors that give rise to the obvious morphological differences between males and females have long been known. Recently however, some less obvious disparities have emerged at the molecular level in the form of sex specific metabolic profiles, where any attempts to attribute these differences to genomic variations in SNPs has failed due to an inability to reproduce findings. This has contributed to a surge in interest for determining how men and women differ at the epigenetic level, something which could be very important when considering that the global epigenetics drug and technologies market is expected to rise in value from US$1.6 billion in 2011, to US$5.7 billion in 20181. While attempts have been made to characterize variations in DNA methylation patterns between the sexes, they have generally been limited in scope, focusing on specific pathways or chromosomes. This prompted Singmann et al to investigate the global DNA methylation patterns across a large population-based cohort, the results of which have now been published.

Using whole blood DNA methylation data from 877 men and 922 women, 391,885 autosomal CpG sites were analysed, identifying 11,010 sex-methylation associations (SMAs). These sites were then validated using three alternate cohorts from varying geographic locations, reducing the number of SMAs to 1,184. Importantly, many of the SMAs not replicated in this validation are not thought to be false positives due to the observation that their sex-associated variations were in a consistent direction. Next, 231 of the validated SMA sites were randomly selected to assess how their locations were distributed across the CpG islands, highlighting that they are over-represented in the CpG island shores; corresponding to the 2 kb region either side of a CpG island.

Singmann et al next wanted to determine how the 1,184 validated SMAs contributed to biological functions. From the original data files, the mRNA expression of 16,904 genes were found to be associated with DNA methylation at CpG sites, 2 of which were located within 1Mb of a validated SMA: the cytokine-inducible SH2-containing protein gene (CISH); and the Ras-related protein (RAB23). The first of these, CISH, codes for a protein that negatively regulates the JAK-STAT signaling pathway with important roles in T-cell function and general immune response. Interestingly, there is evidence that males are more susceptible to infectious diseases, whereas females tend to have higher levels of autoimmune disease, with DNA methylation now likely to influence this. The second gene uncovered, RAB23, corresponds to a small GTPase that acts as a negative regulator of the hedgehog pathway, however the significance of this is less clear, since hedgehog signaling plays a role in embryonic development, in addition to regulating the stem cells involved in maintenance and regeneration in adult tissue.

This study clearly highlighted a large number of differentially methylated CpG sites between the sexes, indicating that future epigenetics based studies would benefit from taking gender into consideration. However, analysis of these sites only revealed two corresponding genes, suggesting that more could have been done to link the results to biological functions. To this end, there needs to be further elucidation of how these sites could act over longer ranges, since only proximal genes within 1Mb were considered.


Original article:
Singmann P, Shem-Tov D, Wahl S, Grallert H, Fiorito G, Shin SY, Schramm K, Wolf P, Kunze S, Baran Y, Guarrera S, Vineis P, Krogh V, Panico S, Tumino R, Kretschmer A, Gieger C, Peters A, Prokisch H, Relton CL, Matullo G, Illig T, Waldenberger M, & Halperin E (2015). Characterization of whole-genome autosomal differences of DNA methylation between men and women. Epigenetics & chromatin, 8 PMID: 26500701


1)      Increased cancer research to drive the epigenetics drugs and diagnostics technologies market globally, 2015 (


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Will Beckman

Will Beckman