Introduction: Early-life stress exposure has been linked to an increased risk for the onset of mental disorders. As another factor, an individual’s genetic make-up may also tip the scale towards health or disease, with certain genetic variants mediating differential susceptibility towards the effects of early-life stress or other experiences. The current study investigated the molecular foundation of individual variation in the response to prenatal stress (PS) exposure in wildtype mice as well as in mice deficient for the serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT). Methods: To meet this end, wildtype C57BL6/J dams were mated with 5-Htt+/- C57BL6/J males, after which they were exposed to restraint stress during the last part of gestation. In adulthood, female 5-HTT-deficient PS offspring and their wildtype littermates as well as age-matched control groups completed a behavioural test-battery, after which gene expression and histone 3 lysine 4 tri-methylation (H3K4me3) enrichment, as a marker of epigenetic programming, were measured in hippocampal tissue. Results: Dependent on the 5-Htt genotype, PS offspring showed decreased social behaviour in the 3-chamber sociability test. Notably, we observed a considerable degree of behavioural variation in the observed effect of PS in this social test, which allowed segregation into socially affected (SA) and socially unaffected (SU) mice. Genome-wide mRNA expression profiling of hippocampal tissue revealed a core set of 23 genes to be associated with genotype-specific variation in social behaviour following PS exposure. Whereas H3K4me3 levels did not show profound global changes in relation to the variable effects of PS exposure on social behaviour, the kinesin family member 14 (Kif14) gene, which displayed increased expression in socially unaffected wildtype mice, did show lower levels of H3K4me3 in those same mice, but not in any of the other groups. Discussion: All in all, differential susceptibility linked to PS exposure displayed 5-Htt genotype-dependent behavioural and transcriptomic profiles, supporting the notion of 5-HT-dependent developmental programming.

Correction to: Nature Cell Biologyhttps://doi.org/10.1038/s41556-023-01194-w. Published online 19 July 2023. In the version of this article originally published, the name of Tianyang Xu was misspelled as Tiangyang Xu. The name has been corrected in the HTML and PDF versions of the article.

Background: Neurodegenerative disorders, including Alzheimer’s disease (AD), have been linked to alterations in tryptophan (TRP) metabolism. However, no studies to date have systematically explored changes in the TRP pathway at both transcriptional and epigenetic levels. This study aimed to investigate transcriptomic, DNA methylomic (5mC) and hydroxymethylomic (5hmC) changes within genes involved in the TRP and nicotinamide adenine dinucleotide (NAD) pathways in AD, using three independent cohorts. Methods: DNA derived from post-mortem middle temporal gyrus (MTG) tissue from AD patients (n = 45) and age-matched controls (n = 35) was analyzed, along with DNA derived from blood samples from two independent cohorts: the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) cohort (n = 96) and the Dutch BioBank Alzheimer Center Limburg (BBACL) cohort (n = 262). Molecular profiling, including assessing mRNA expression and DNA (hydroxy)methylation levels, was conducted using HumanHT-12 v4 Expression BeadChip and HM 450 K BeadChip arrays, respectively. Functional interactions between genes and identification of common phenotype-specific positive and negative elementary circuits were conducted using computational modeling, i.e. gene regulatory network (GRN) and network perturbational analysis. DNA methylation of IDO2 (cg11251498) was analyzed using pyrosequencing. Results: Twelve TRP- and twenty NAD-associated genes were found to be differentially expressed in the MTG of AD patients. Gene sets associated in the kynurenine pathway, the most common TRP pathway, and NAD pathway, showed enrichment at the mRNA expression level. Downstream analyses integrating data on gene expression, DNA (hydroxy)methylation, and AD pathology, as well as GRN and network perturbation analyses, identified IDO2, an immune regulatory gene, as a key candidate in AD. Notably, one CpG site in IDO2 (cg11251498) exhibited significant methylation differences between AD converters and non-converters in the AgeCoDe cohort. Conclusion: These findings reveal substantial transcriptional and epigenetic alterations in TRP- and NAD-pathway-associated genes in AD, highlighting IDO2 as a key candidate gene for further investigation. These genes and their encoded proteins hold potential as novel biomarkers and therapeutic targets for AD.

The Human BioMolecular Atlas Program (HuBMAP) aims to create a multi-scale spatial atlas of the healthy human body at single-cell resolution by applying advanced technologies and disseminating resources to the community. As the HuBMAP moves past its first phase, creating ontologies, protocols and pipelines, this Perspective introduces the production phase: the generation of reference spatial maps of functional tissue units across many organs from diverse populations and the creation of mapping tools and infrastructure to advance biomedical research.