Uncovering mechanisms for the transmission of early life programming effects across generations

Uncovering mechanisms for the transmission of early life programming effects across generations

Section of testis

Epidemiological studies have shown a link between exposure to an adverse environment in early life and an increased risk of cardiometabolic and neurodevelopmental disease. These ‘programmed’ effects are transmissible across generations through both male and female lines (Drake et al). Although transmission through the female line could be explained by changes in maternal physiology or behaviour, transmission through the male line implies effects on the germline (Drake & Liu). A number of studies have suggested that ‘epigenetic mechanisms’ including changes in germline DNA methylation, histone modifications or small RNAs may account for the transmission of effects across generations although such changes would need to escape the extensive epigenetic reprogramming which occurs in the developing germline (Rose et alRose et al). In collaboration with Richard Meehan and Andreas Heger and Tom Smith, we are profiling these modifications in detail in germ cells and sperm (Figure 1) using techniques which allow us to obtain highly purified cell populations (Figure 2). Using these techniques, we have recently shown that exposure to maternal obesity is associated with adverse effects on offspring metabolism in two subsequent generations, however this is not associated with changes in the intratesticular germ cell transcriptome (Chambers et al) (Figure 3). Our ongoing work involves studies of DNA methylation, histone modifications and small RNAs in this and other models.

Figure 1. Section through testis showing spermatogenesis

Figure 2. Profilingpure populations of germ cells. A. Developing ovaries with EGFP-labelled germ cells. B. Developing testes with EGFP-labelled germ cells

Figure 3. mRNA-seq data from purified germ cells