Thursday 14 January 2021, 1pm - 2pm
Using human genetics to understand the aetiology of reproductive ageing and its links to later life diseases
Staša Stanković (MRC Epidemiology Unit)
Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis
Juan Castillo-Fernandez (Babraham Institute)
Chair: Dr Claire Senner (PDN/CTR)
This seminar will take place on Zoom; to receive the meeting details, please register first at https://zoom.us/meeting/register/tJMkc-mtpzgjH9ZVQtaoe7djTeUU6kNiBe96.
The Early Researchers Seminar Series (ERSS) is a platform for PhD Students and early career researchers (ECRs) at the University of Cambridge with research foci on reproduction to share and discuss their research with other academics from a range of disciplines also researching reproduction at the University. Seminars are held on Zoom on the second Thursday of every month, 1pm - 2pm. For more information, and for the full 2020 - 2021 programme, please see the main ERSS page.
Speakers and abstracts
Using human genetics to understand the aetiology of reproductive ageing and its links to later life diseases
Staša Stanković (MRC Epidemiology Unit)
Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. The current markers used in clinical practice are not precise predictors of the menopause timing, thus not allowing informed reproductive choices for women and early treatments. By combining state-of-the-art genomic technologies with human population-based studies, we identified 290 common genetic variants that govern ovarian ageing and act on clinical extremes of age at natural menopause. Identified loci implicate a broad range of DNA damage response (DDR) processes. We demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice, acting across the life-course to shape the ovarian reserve and its rate of depletion. Causal inference analyses using identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. Our current work that involves exome level data will be focused towards the identification of low-frequency and rare variants not well captured by current array-based data. Our findings provide insight into the mechanisms governing ovarian ageing and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Staša Stanković is a second year PhD student in Genomic Medicine at the MRC Epidemiology Unit, University of Cambridge, supervised by Dr John Perry, Prof Ken Ong and Dr Hana Lango Allen. Her research is focused on understanding the genetic architecture behind reproductive ageing, as well as biological mechanisms that link early life growth and reproductive ageing to later life cardio-metabolic health outcomes. This is achieved using genetic approaches in large-scale population studies, including application of high-throughput sequence data, supported by further functional insights using complementary approaches in animal and cellular models through collaborations. Prior to joining the Unit, Staša was awarded an MPhil in Medical Science from the University of Cambridge, Wellcome Trust Sanger Institute. She gained further research experience at the Department of Physiology, Development and Neuroscience (Cambridge), and was involved in the development of “Congenica Neuro”, new generation product for the genetic analysis of individuals with neurodevelopmental diseases as part of Congenica, genomic medicine company.
Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis
Juan Castillo-Fernandez (Babraham Institute)
Advancing maternal age causes a progressive reduction in fertility. The decline in developmental competence of the oocyte with age is likely to be a consequence of multiple contributory factors. Loss of epigenetic quality of the oocyte could impair early developmental events or programme adverse outcomes in offspring that manifest only later in life. Here, we undertake joint profiling of the transcriptome and DNA methylome of individual oocytes from reproductively young and old mice. We find reduced complexity as well as increased variance in the transcriptome of oocytes from aged females. This transcriptome heterogeneity is reflected in the identification of discrete sub-populations. Oocytes with a transcriptome characteristic of immature chromatin configuration (NSN) clustered into two groups: one with reduced developmental competence, as indicated by lower expression of maternal-effect genes; and one with a young-like transcriptome. Oocytes from older females had on average reduced CpG methylation, but the characteristic bimodal methylation landscape of the oocyte was preserved. Germline differentially methylated regions of imprinted genes were appropriately methylated irrespective of age. For the majority of differentially expressed transcripts, the absence of correlated methylation changes suggests a post-transcriptional basis for most age-related effects on the transcriptome. However, we did find differences in gene-body methylation at which there were corresponding changes in gene expression, indicating age-related effects on transcription that translate into methylation differences. Interestingly, oocytes varied in expression and methylation of these genes, which could contribute to variable competence of oocytes or penetrance of maternal age-related phenotypes in offspring.
Juan Castillo-Fernandez completed a B.Sc. in Biotechnology Engineering at ITESM (Mexico). At this time, he joined the Department of Computational Genomics at the National Institute of Genomic Medicine (INMEGEN) as an undergraduate research fellow. In 2018, he received a Ph.D. from King’s College London (UK). As part of his doctoral studies, he investigated the consequences of in vitro fertilisation on the methylome of newborns. In 2019, with experience in multi-omic analysis, Juan joined the Kelsey Lab of the Epigenetics research programme at the Babraham Institute where he uses single-cell multi-omic and genome-wide analysis to investigate epigenetic processes in the oocyte. Working closely with experimental colleagues, Juan has characterised the effects of ageing on the transcriptional and epigenetic profiles of mouse oocytes, as well as the effects of ageing and diminished ovarian reserve on the epigenetic profile of human granulosa cells.
