Fear Stress During Pregnancy Affects Placental m6A-Modifying Enzyme Expression and Epigenetic Modification Levels

Abstract

As the hub connecting mother and offspring, the placenta’s normal development is vital for fetal growth. Fear stress can cause some structural alterations in the placenta and affect placental development and function. N6-methyladenosine (m6A) is the most common mRNA modification and is involved in regulating the development of the placenta and embryo. There are no reports on the potential role of m6A modification in placental damage caused by fear stress during pregnancy. In this study, we demonstrated that fear stress during pregnancy increases the levels of methylated enzymes (METTL3, METTL14, and WTAP), decreases the levels of demethylase FTO, and increases the overall methylation levels in the placenta of pregnant rats. MeRIP-seq data analysis revealed 22,010 m6A peaks associated with 12,219 genes in the placenta of the model and 21,060 m6A peaks associated with 11,730 genes in the placenta of the control. The peaks were mainly concentrated in the coding region and the 3ʹ untranslated region. In addition, 50 genes with abnormal modification and expression (double aberrant genes) were screened out by combining MeRIP-seq and RNA-seq data. Mefv, Erbb2, and Cgas were selected from 50 double aberrant genes, and MeRIP-qPCR and real-time quantitative polymerase chain reaction were used to verify their modification and expression levels. Our findings suggest that m6A modifications play an important role in placental dysfunction induced by fear stress during pregnancy.

Prenatal Lipopolysaccharide Exposure Alters Hepatic Drug-Metabolizing Enzyme Expression in Mouse Offspring via Histone Modifications

“…Future studies will also be performed to investigate the H3K4me3 and H3K27me3 levels in promoters of other DMEs. Notably, recent studies show that N6-methyl-adenosine (m6A) modification contributes to adverse pregnancy outcomes [ 48 , 49 ]. Moreover, m6A modification is involved in the regulation of DMEs [ 50 , 51 ].…”

N6-methyladenosine modifications in maternal-fetal crosstalk and gestational diseases

“…External stimuli such as fear stress can cause significant harm to pregnant women and increase the risk of fetal malformations and placental structural alterations ( Tsui et al, 2006 ; Mizrak and Kabakci, 2021 ). In pregnant rats, fear stress during gestation significantly reduces placental weight and offspring viability ( Wang et al, 2022a ). Stress also increases the expression levels of METTL3, METTL14 and WTAP, decreases the level of FTO, and leads to a higher overall m 6 A level in placental tissues ( Wang et al, 2022a ).…”

“…In pregnant rats, fear stress during gestation significantly reduces placental weight and offspring viability ( Wang et al, 2022a ). Stress also increases the expression levels of METTL3, METTL14 and WTAP, decreases the level of FTO, and leads to a higher overall m 6 A level in placental tissues ( Wang et al, 2022a ). While, stress has no obvious change in the distribution of m 6 A-enriched regions and motif.…”

“…While, stress has no obvious change in the distribution of m 6 A-enriched regions and motif. Based on MeRIP-seq data, fear stress mainly affects m 6 A-modified genes involved in utero embryonic development, protein stabilization, angiogenesis and embryonic digit morphogenesis ( Wang et al, 2022a ). Similar changes are also found in brain development and adult neurons ( Widagdo et al, 2016 ; Walters et al, 2017 ).…”

Bioinformatics study and experimental validation of METTL3 regulation of immune-related genes affecting placental vascular development

“…According to the results of MeRIP-seq data analysis, we found the level of METTL3 gene was signi cantly down-regulated in the placentas from pregnant rats of fear stress. We developed the gestational fear stress model using a modi ed standard electroshock method (12), which was repeated daily from GD1 to GD19.…”