Loreen Thürmann

Environment-induced epigenetic reprogramming in genomic regulatory elements in smoking mothers and their children

Epigenetic mechanisms have emerged as links between prenatal environmental exposure and disease risk later in life. Here, we studied epigenetic changes associated with maternal smoking at base pair resolution by mapping DNA methylation, histone modifications, and transcription in expectant mothers and their newborn children. We found extensive global differential methylation and carefully evaluated these changes to separate environment associated from genotype‐related DNA methylation changes. Differential methylation is enriched in enhancer elements and targets in particular “commuting” enhancers having multiple, regulatory interactions with distal genes. Longitudinal whole‐genome bisulfite sequencing revealed that DNA methylation changes associated with maternal smoking persist over years of life. Particularly in children prenatal environmental exposure leads to chromatin transitions into a hyperactive state. Combined DNA methylation, histone modification, and gene expression analyses indicate that differential methylation in enhancer regions is more often functionally translated than methylation changes in promoters or non‐regulatory elements. Finally, we show that epigenetic deregulation of a commuting enhancer targeting c‐Jun N‐terminal kinase 2 (JNK2) is linked to impaired lung function in early childhood.

Prenatal maternal stress and wheeze in children: novel insights into epigenetic regulation

Psychological stress during pregnancy increases the risk of childhood wheeze and asthma. However, the transmitting mechanisms remain largely unknown. Since epigenetic alterations have emerged as a link between perturbations in the prenatal environment and an increased disease risk we used whole genome bisulfite sequencing (WGBS) to analyze changes in DNA methylation in mothers and their children related to prenatal psychosocial stress and assessed its role in the development of wheeze in the child. We evaluated genomic regions altered in their methylation level due to maternal stress based of WGBS data of 10 mother-child-pairs. These data were complemented by longitudinal targeted methylation and transcriptional analyses in children from our prospective mother-child cohort LINA for whom maternal stress and wheezing information was available (n = 443). High maternal stress was associated with an increased risk for persistent wheezing in the child until the age of 5. Both mothers and children showed genome-wide alterations in DNA-methylation specifically in enhancer elements. Deregulated neuroendocrine and neurotransmitter receptor interactions were observed in stressed mothers and their children. In children but not in mothers, calcium- and Wnt-signaling required for lung maturation in the prenatal period were epigenetically deregulated and could be linked with wheezing later in children’s life.

Increased vitamin D levels at birth and in early infancy increase offspring allergy risk—evidence for involvement of epigenetic mechanisms

To the Editor: Although a beneficial effect of vitamin D on health is widely accepted, its role in allergy development has been controversial. Both allergy-preventing and allergy-promoting effects have been reported. Thus, a deeper mechanistic understanding of how vitamin D is related to the regulation of immune reactivity and allergic inflammation is required. Vitamin D was shown to modify gene expression through binding of the vitamin D receptor to vitamin D response elements. However, only 26% of the genes identified as regulated by vitamin D have a vitamin D response element in proximity to their transcription start site (TSS), indicating that additional mechanisms are involved in the transcriptional control by vitamin D. As an additional mechanism, epigenetically mediated transcriptional deregulation through vitamin D–induced changes in DNA methylation was suggested. Here, we studied DNA-methylation pattern on a genomewide scale at base-pair resolution in healthy newborn children with high and low vitamin D levels to elucidate the role of vitamin D in epigenetic programming of an allergy-protective or allergypromoting immune reactivity. Within the LINA (Lifestyle and environmental factors and their Influence on Newborns Allergy risk) mother-child cohort, differential DNA methylation was assessed by using whole genome bisulfite sequencing in 6 cord blood samples comparing 3 children with high to 3 children with low

Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications

Background: Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy‐promoting effects in children because of exposure to plasticizers, such as phthalates, findings of previous studies are inconsistent and lack mechanistic information. Objective: We investigated the effect of maternal phthalate exposure on asthma development in subsequent generations and their underlying mechanisms, including epigenetic alterations. Methods: Phthalate metabolites were measured within the prospective mother‐child cohort Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk (LINA) and correlated with asthma development in the children. A murine transgenerational asthma model was used to identify involved pathways. Results: In LINA maternal urinary concentrations of mono‐n‐butyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine transgenerational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease‐promoting effect was mediated by BBP‐induced global DNA hypermethylation in CD4+ T cells of the offspring because treatment with a DNA‐demethylating agent alleviated exacerbation of allergic airway inflammation. Thirteen transcriptionally downregulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA‐3 repressor zinc finger protein 1 (Zfpm1) emerged as a potential mediator of the enhanced susceptibility for TH2‐driven allergic asthma. Conclusion: These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in TH2 differentiation through epigenetic alterations.

Suppression of indoleamine-2,3-dioxygenase 1 expression by promoter hypermethylation in ER-positive breast cancer

ABSTRACT Kynurenine formation by tryptophan-catabolic indoleamine-2,3-dioxygenase 1 (IDO1) plays a key role in tumor immune evasion and inhibition of IDO1 is efficacious in preclinical models of breast cancer. As the response of breast cancer to immune checkpoint inhibitors may be limited, a better understanding of the expression of additional targetable immunomodulatory pathways is of importance. We therefore investigated the regulation of IDO1 expression in different breast cancer subtypes. We identified estrogen receptor α (ER) as a negative regulator of IDO1 expression. Serum kynurenine levels as well as tumoral IDO1 expression were lower in patients with ER-positive than ER-negative tumors and an inverse relationship between IDO1 and estrogen receptor mRNA was observed across 14 breast cancer data sets. Analysis of whole genome bisulfite sequencing, 450k, MassARRAY and pyrosequencing data revealed that the IDO1 promoter is hypermethylated in ER-positive compared with ER-negative breast cancer. Reduced induction of IDO1 was also observed in human ER-positive breast cancer cell lines. IDO1 induction was enhanced upon DNA demethylation in ER-positive but not in ER-negative cells and methylation of an IDO1 promoter construct reduced IDO1 expression, suggesting that enhanced methylation of the IDO1 promoter suppresses IDO1 in ER-positive breast cancer. The association of ER overexpression with epigenetic downregulation of IDO1 appears to be a particular feature of breast cancer as IDO1 was not suppressed by IDO1 promoter hypermethylation in the presence of high ER expression in cervical or endometrial cancer.

Early-onset childhood atopic dermatitis is related to NLRP2 repression

Capsule summary Early-onset atopic dermatitis (AD) related repression of the immune regulatory NLRP2 is driven by promoter hypermethylation starting already at time of birth providing an early opportunity to modulate innate immunity to potentially mitigate AD development.