Stress is something we are all too familiar with. When it comes down to a stressful situation, it seems that there are almost two types of people: those stricken by anxiety and depression, and those who keep on walking on as if nothing has happened. But what shapes such a distinction between people? One contributing factor is early-life maternal care. With over five decades of evidence, rodent models have served as an important proxy for humans, where licking and grooming of a pup by their mother mirrors the contact that a human mother provides to her baby.
While much of the research into maternal care has focused on risk factors for anxiety and depression, the protective factors that shape resilience to stress remain underexplored. Furthermore, maternal care studies have primarily focused on a few select genes. Now, new findings from the lab of Janine LaSalle at the University of California, Davis, demonstrate for the first time that pups receiving extra maternal care exhibit genome-wide differences in DNA methylation as well as microRNA (miRNA) and gene expression in the stress center of the brain (the hypothalamus).
To gain an integrative genome-wide perspective, the team employed whole-genome bisulfite sequencing (WGBS), a genome-wide miRNA assay, and RNA-seq to analyze the hypothalamus of male rat pups (post-natal day 9) that received extra maternal care and compared this data to matched controls receiving standard levels of maternal care. Here’s what they uncovered:
- 9,439 differentially methylated regions (DMRs), which are enriched for CTCF binding sites, and map to genes related to stress response and neurodevelopment
- 2,464 differentially expressed genes that are enriched for the mTOR signaling pathway, including binding sites for the Elk1 transcription factor
- While the study discovered only five differentially expressed miRNAs, bioinformatic prediction suggests that these miRNAs target 127 of the 2,464 differentially expressed genes
- Furthermore, a non-coding isoform of Ube3a, which functions as a miRNA sponge, becomes down-regulated, while a predicted target miRNA (mir-542-5p) becomes up-regulated
- Integration of the three diverse data sets revealed a suite of 20 genes displaying differences on all three levels
- While some genes have been previously implicated in stress responses, most represent novel finds and relate to diverse functions that can potentially shape resilience to stress
Overall, this exploratory study represents the first genome-wide analysis of DNA methylation following extra maternal care, where it uncovers a genome-wide profile of differences. Additionally, the in-depth analysis provides multiple novel candidates for future functional experimentation.
Senior Author Dag Yasui concludes with his outlook that, “If nothing else, our findings illustrate how important maternal care is with genome-wide alterations affecting a range of cellular processes in the augmented newborn. Most importantly, can new therapies based on the protective modifications we have identified be employed in people who are suffering from anxiety and depression? If so the benefits to society are enormous as it is estimated that one in five people experience mental health disorders in a given year.”
To see why you should appreciate the care provided by your mother, head over to Epigenetics, April 2018.