The mRNA "epitranscriptome": delineating its role in regulating gene expression in mammalian oocytes and the impact of assisted reproductive technolog
Lead Research Organisation:
University of Edinburgh
Department Name: MRC Centre for Reproductive Health
Abstract
Infertility affects roughly 1 in 6 couples worldwide, with 3 million babies having being born using assisted reproduction technologies (ART) by 2018. However, success rates lie at only 20-35% per cycle, with NHS resource restrictions meaning that the number of cycles per couple is limited. After age 42, success rates for women plummet to 4%, which is problematic as women are increasingly delaying childbirth. Moreover there is also an increased treatment need from cancer survivors as chemotherapeutics can negatively affect fertility. Thus to be able to predict individual fertility and to improve treatments for those with compromised fertility, there is a need to understand the basic mechanisms that underpin the survival and development of germ cells.
In roughly 50% of cases the partner with compromised fertility is female. Women are born with a finite number of oocytes, with menopause occurring when these become depleted. Oocytes are maintained in "follicles" in close association with support cells known as granulosa cells. Follicles from this pool become activated and grow prior to ovulation. The survival, growth and development of follicles relies on intricate control of gene expression.
The advent of new sequencing technologies now offers the possibility of understanding the complexity of gene expression that underlies the growth, maturation, fertilisation and development of early embryos, in detail previously unimaginable. Such studies have revealed differences in the transcriptome (or complement of mRNAs) between in vivo and in vitro matured oocytes. However, post-transcriptional control mechanisms, such as regulated mRNA translation/stability are equally key to maintaining fertility but much less well understood.
Importantly, work in other fields particularly from those studying cancer, cell differentiation and the brain has uncovered an exciting new mechanism of regulating mRNA translation/stability, launching a new field known as "epitranscriptomics" in analogy to the field of epigenetics. This advance came from Next Generation Sequencing (NGS) which revealed that modifications (methylations, most frequently m6A) of the nucleotides of mRNAs occur frequently. Whilst DNA methylation and its role in epigenetics is well understood, the function of these modifications in RNA is only just starting to emerge. However they appear to play critical roles on controlling the translation/stability of mRNAs by affecting the binding of RNA-binding proteins.
Importantly, the impact of this type of regulation on female fertility in mammals remains to be explored. Recent work has shown it is critical for the oocyte to zygote transition in zebrafish (1) and meiotic progression during mouse spermatogenesis (2), supporting the hypothesis that it will also be important for female fertility in mammals.
Thus this project will use cutting-edge NGS applications to map the epitranscriptome of developing oocytes and compare them to those developed in vitro, to understand the impact of ART technologies on gene expression. This will be done in mouse but where appropriate, findings will be translated in humans using unique resources available within Edinburgh.
In roughly 50% of cases the partner with compromised fertility is female. Women are born with a finite number of oocytes, with menopause occurring when these become depleted. Oocytes are maintained in "follicles" in close association with support cells known as granulosa cells. Follicles from this pool become activated and grow prior to ovulation. The survival, growth and development of follicles relies on intricate control of gene expression.
The advent of new sequencing technologies now offers the possibility of understanding the complexity of gene expression that underlies the growth, maturation, fertilisation and development of early embryos, in detail previously unimaginable. Such studies have revealed differences in the transcriptome (or complement of mRNAs) between in vivo and in vitro matured oocytes. However, post-transcriptional control mechanisms, such as regulated mRNA translation/stability are equally key to maintaining fertility but much less well understood.
Importantly, work in other fields particularly from those studying cancer, cell differentiation and the brain has uncovered an exciting new mechanism of regulating mRNA translation/stability, launching a new field known as "epitranscriptomics" in analogy to the field of epigenetics. This advance came from Next Generation Sequencing (NGS) which revealed that modifications (methylations, most frequently m6A) of the nucleotides of mRNAs occur frequently. Whilst DNA methylation and its role in epigenetics is well understood, the function of these modifications in RNA is only just starting to emerge. However they appear to play critical roles on controlling the translation/stability of mRNAs by affecting the binding of RNA-binding proteins.
Importantly, the impact of this type of regulation on female fertility in mammals remains to be explored. Recent work has shown it is critical for the oocyte to zygote transition in zebrafish (1) and meiotic progression during mouse spermatogenesis (2), supporting the hypothesis that it will also be important for female fertility in mammals.
Thus this project will use cutting-edge NGS applications to map the epitranscriptome of developing oocytes and compare them to those developed in vitro, to understand the impact of ART technologies on gene expression. This will be done in mouse but where appropriate, findings will be translated in humans using unique resources available within Edinburgh.
Organisations
People |
ORCID iD |
| Nicola Gray (Primary Supervisor) | |
| Triin Õunapuu (Student) |