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. 2023 Aug 23;21(1):173.
doi: 10.1186/s12915-023-01662-7.

Sexually dimorphic methylation patterns characterize the placenta and blood from extremely preterm newborns

Hudson P Santos Jr  1 , Adam E Enggasser  2 , Jeliyah Clark  2   3 , Kyle Roell  2   3 , Vasyl Zhabotynsky  2 , William Adam Gower  4 , Diana Yanni  5 , Nou Gao Yang  6 , Lisa Washburn  6 , Semsa Gogcu  6 , Carmen J Marsit  7 , Karl Kuban  8 , T Michael O'Shea  4 , Rebecca C Fry  2   3   9
Affiliations

Sexually dimorphic methylation patterns characterize the placenta and blood from extremely preterm newborns

Hudson P Santos Jr et al. BMC Biol. .

Abstract

Background: Health outcomes among children born prematurely are known to be sexually dimorphic, with male infants often more affected, yet the mechanism behind this observation is not clear. CpG methylation levels in the placenta and blood also differ by sex and are associated with adverse health outcomes. We contrasted CpG methylation levels in the placenta and neonatal blood (n = 358) from the Extremely Low Gestational Age Newborn (ELGAN) cohort based on the EPIC array, which assays over 850,000 CpG sites across the epigenome. Sex-specific epigenome-wide association analyses were conducted for the placenta and neonatal blood samples independently, and the results were compared to determine tissue-specific differences between the methylation patterns in males and females. All models were adjusted for cell type heterogeneity. Enrichment pathway analysis was performed to identify the biological functions of genes related to the sexually dimorphic CpG sites.

Results: Approximately 11,500 CpG sites were differentially methylated in relation to sex. Of these, 5949 were placenta-specific and 5361 were blood-specific, with only 233 CpG sites overlapping in both tissues. For placenta-specific CpG sites, 90% were hypermethylated in males. For blood-specific CpG sites, 95% were hypermethylated in females. In the placenta, keratinocyte differentiation biological pathways were enriched among the differentially methylated genes. No enrichment pathways were observed for blood.

Conclusions: Distinct methylation patterns were observed between male and female children born extremely premature, and keratinocyte differentiation pathways were enriched in the placenta. These findings provide new insights into the epigenetic mechanisms underlying sexually dimorphic health outcomes among extremely premature infants.

Keywords: Blood; Child health; Epigenetics; Placenta; Preterm birth.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The left side shows Manhattan plots with the distribution of autosomal sexually dimorphic CpG sites in (A) placenta (n = 6182) and (B) day 1 blood (n = 5594). The right side shows the QQ plots visualizing displaying the genomic inflation for placenta (λgc = 2.74) and blood (λgc = 2.76)
Fig. 2
Fig. 2
Comparison of CpG site methylation associated with sex between the placenta and blood. A total of 11,543 CpG sites displayed sexually dimorphic patterns in methylation: 5949 of these sites were found only in the placenta, and 5361 were found only in the blood sample. Of all sites, 233 (2.0%) were differentially methylated in both tissues
Fig. 3
Fig. 3
Distribution of the average beta value differences between males and females for all sexually dimorphic CpG sites. Beta differences greater than 0 represent hypermethylation in males, and beta differences below 0 represent hypermethylation in females. Note the hypermethylation in males in placenta-only CpG sites and hypermethylation in females in blood-only CpG sites
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