Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro.

Microglia, the macrophages of the brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer's disease. These cells adopt distinct transcriptional subtypes known as states. Understanding state function, especially in human microglia, has been elusive owing to a lack of tools to model and manipulate these cells. Here, we developed a platform for modeling human microglia transcriptional states in vitro. We found that exposure of human stem-cell-differentiated microglia to synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated transcriptional diversity that mapped to gene signatures identified in human brain microglia, including disease-associated microglia, a state enriched in neurodegenerative diseases. Using a new lentiviral approach, we demonstrated that the transcription factor MITF drives a disease-associated transcriptional signature and a highly phagocytic state. Together, these tools enable the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.

Chimpanzee Extraversion scores vary with epigenetic modification of dopamine receptor gene D2 (DRD2) and early rearing conditions.

Chimpanzees have consistent individual differences in behaviour, also referred to as personality. Similar to human personality structure, five dimensions are commonly found in chimpanzee studies that show evidence for convergent and predictive validity (Dominance, Openness, Extraversion, Agreeableness, and Reactivity/Undependability). These dimensions are to some extent heritable, indicating a genetic component that explains part of the variation in personality scores, but are also influenced by environmental factors, such as the early social rearing background of the individuals. In this study, we investigated the role of epigenetic modification of the dopamine receptor D2 gene (DRD2) as a potential mechanism underlying personality variation in 51 captive chimpanzees. We used previously collected personality trait rating data and determined levels of DRD2 CpG methylation in peripheral blood samples for these same individuals. Results showed that DRD2 methylation is most strongly associated with Extraversion, and that varying methylation levels at specific DRD2 sites are associated with changes in Extraversion in nursery-reared, but not mother-reared, individuals. These results highlight the role of dopaminergic signalling in chimpanzee personality, and indicate that environmental factors, such as social experiences early in life, can have long-lasting behavioural effects, potentially through modification of the epigenome. These findings add to the growing evidence demonstrating the importance of the experience-dependent methylome for the development of complex social traits like personality.

Age-associated epigenetic change in chimpanzees and humans.

Methylation levels have been shown to change with age at sites across the human genome. Change at some of these sites is so consistent across individuals that it can be used as an 'epigenetic clock' to predict an individual's chronological age to within a few years. Here, we examined how the pattern of epigenetic ageing in chimpanzees compares with humans. We profiled genome-wide blood methylation levels by microarray for 113 samples from 83 chimpanzees aged 1-58 years (26 chimpanzees were sampled at multiple ages during their lifespan). Many sites (greater than 65 000) showed significant change in methylation with age and around one-third (32%) of these overlap with sites showing significant age-related change in humans. At over 80% of sites showing age-related change in both species, chimpanzees displayed a significantly faster rate of age-related change in methylation than humans. We also built a chimpanzee-specific epigenetic clock that predicted age in our test dataset with a median absolute deviation from known age of only 2.4 years. However, our chimpanzee clock showed little overlap with previously constructed human clocks. Methylation at CpGs comprising our chimpanzee clock showed moderate heritability. Although the use of a human microarray for profiling chimpanzees biases our results towards regions with shared genomic sequence between the species, nevertheless, our results indicate that there is considerable conservation in epigenetic ageing between chimpanzees and humans, but also substantial divergence in both rate and genomic distribution of ageing-associated sites. This article is part of the theme issue 'Evolution of the primate ageing process'.