Two new studies published in Nature and Molecular Cell have identified roles for RNA modification in the control of egg cell development in mammals.
The first study found that enzymes TUT4 and TUT7 modify messenger RNA (mRNA).
Messenger RNA (mRNA) is the molecule that decodes DNA to produce the proteins that make up cells. The profile of mRNAs present in the mature egg cell, called the maternal transcriptome, is the molecular blueprint that instructs early animal life, before and after fertilisation of the egg.
The correct composition and use of the maternal transcriptome is essential for egg competence, the ability of an egg to generate an embryo and sustain the cycle of life. However, the mechanisms by which the maternal transcriptome is built and initially used are not fully understood.
The study, led by CRM Associate Director Professor Dónal O’Carroll, showed that TUT4 and TUT7 define the content of the transcriptome by modifying the end of the mRNA molecules through a process called Uridylation.
mRNA is protected from degradation by a long tail of adenosine monophosphates (a poly(A) tail). Uridylation was found particularly in mRNAs with a very short poly(A) tail.
The authors suggest that these short poly(A) tails act as a signal for TUT4 and TUT7 uridylation. As the egg cell (or oocyte) develops, uridylation tags very short poly(A) tail mRNA to be discarded.
The research team used female mice in which the genes for TUT4 and TUT7 were deleted. When mice were deficient in TUT4 and TUT7, this caused accumulation of mRNA normally discarded, disrupting normal oocyte development and blocking fertilisation.
In an associated study, the same research team highlighted the importance of a key protein (YTHDF2) that regulates mRNA that is chemically modified with methyl groups. YTHDF2 was shown to be necessary for oocytes to function correctly in mice by fine-tuning the composition of mature maternal transcriptome once the eggs prepare for fertilization. The protein was also shown to be necessary for early development of fertilised mouse eggs.
Professor Dónal O’Carroll said:
“These works are exciting because they are the first to show the importance of RNA-modification in the construction and reading of life’s early blueprint. We have identified two new pathways that underpin egg competence and are essential for the propagation of mammalian life”
The studies, funded by the Wellcome Trust, were carried out in collaboration with researchers at the University of Cambridge and in Italy and Germany.
Morgan et al (2017). mRNA 3′ uridylation and poly(A) tail length sculpt the mammalian maternal transcriptome. Nature, 548, 347–351 (17 August 2017). doi: 10.1038/nature23318
Ivanova et al (2017). The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence. Molecular Cell, 67(6), 903-905 (21 September 2017). doi: 10.1016/j.molcel.2017.08.003
Zhao and He (2017). “Gamete On” for m6A: YTHDF2 Exerts Essential Functions in Female Fertility. Molecular Cell, 67(6), 903-905 (21 September 2017).