Sperm epigenome-mediated transmission of information on father’s acquired metabolic disorder to offspring
Recent research using animal models has shown that father’s acquired traits and conditions can be transmitted to the next generation(s) through the process of epigenetic inheritance. The health of subsequent generations may therefore depend on the health status of the future father at the time of conception, and it is likely that epigenetic inheritance contributes to the increased prevalence of non-communicable diseases, such as diabetes and other metabolic disorders in human populations. Understanding the contribution of epigenetic inheritance in the etiology of metabolic disorders has therefore major public health relevance.
The mechanisms responsible for paternal epigenetic inheritance involve changes in the sperm epigenome, including DNA methylation, histone modifications, and the action of non-coding RNAs (ncRNAs). The current consensus is that non-genetic inheritance involves the interplay between all these epigenetic mechanisms. Animal studies have provided particularly strong evidence on the role of certain small ncRNAs (sncRNAs) in sperm as carriers of epigenetic information on father’s acquired conditions. Mature sperm are largely transcriptionally inactive, but they retain a specific set of sncRNAs that are either produced in the germline, or are delivered to sperm from epididymal epithelial cells during the sperm transit through the epididymal duct. Different environmental exposures, including dietary and lifestyle factors, can modify the levels of sperm sncRNAs, particularly tRNA-derived small RNAs (tsRNAs), PIWI-interacting RNAs (piRNAs) and miRNAs, and these changes can transmit the information on father’s acquired condition to the offspring by modulating gene expression in zygotes.
It is still unknown how information about environmentally-induced phenotypic changes are converted into changes in sperm epigenome. Furthermore, we need more detailed information about the stability of environmentally-induced changes, i.e. whether they can be reversed, and would this improve offspring health.
We use mouse as a model to investigate the effects of high-fat diet (HFD)-induced metabolic disorder on offspring health. Particularly, we are interested in exploring the roles of sperm sncRNAs as intergenerational carriers of the information. We also actively collaborate with the human cohort studies in the Centre for Population Health Research (https://www.popc.utu.fi/) to translate our findings to human health. Specifically, our aim is to clarify 1) the establishment of sperm sncRNA profile during differentiation and sperm maturation, 2) the effects of mouse metabolic health and the timing of father’s HFD exposure on sperm sncRNA profile, and 3) the father’s HFD-induced changes in the transcriptome profiles and epigenome of male germline of the offspring. We have a large number of existing RNA sequencing datasets available from our previous mouse experiments, but we are also interested in setting up new multigenerational mouse experiments to answer our research questions.
We are looking for a postdoc with a degree in life sciences, or a related field. Strong expertise in biomedical research and mouse experimentation is required, and the research also requires understanding/expertise in bioinformatics analyses, especially RNAseq and small-RNAseq analyses.
Selected publications:
- Chen, Q., Yan, W. & Duan, E. Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat. Rev. Genet. 17, 733–743 (2016).
- Perez, M. F. & Lehner, B. Intergenerational and transgenerational epigenetic inheritance in animals. Nature Cell Biology vol. 21 143–151 (2019).
- Lehtiniemi, T., Mäkelä, M. & Kotaja, N. Small Non-Coding RNAs and Epigenetic Inheritance. in Beyond Our Genes 209–230 (Springer International Publishing, 2020). doi:10.1007/978-3-030-35213-4_11.
- Tomar, A. et al. Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs. Nature (2024) doi:10.1038/S41586-024-07472-3.
- Crisóstomo, L. et al. Testicular ‘Inherited Metabolic Memory’ of Ancestral High-Fat Diet Is Associated with Sperm sncRNA Content. Biomedicines 10, 909 (2022).