RNA epigenetic marks affect transcriptome switching during early embryonic development
Boxuan Simen Zhao, Xiao Wang, Alana V. Beadell, Robert K. Ho, Chuan He
The University of Chicago, Chicago, IL, USA
Over 100 types of chemical modifications exist on RNA and carry out distinct functions. Among these RNA modifications, m6A is the most abundant epigenetic mark on mRNA and plays critical regulatory roles in RNA metabolism. Functioning through specific reader proteins, m6A notably increases mRNA translation efficiency or accelerates the decay of marked transcripts, both critical for the change of gene expression profile and cell state. However, the involvement of m6A in complex biological processes has not been well explored, particularly during cell differentiation and embryonic development.
Occurring at the early stage of embryonic development, the maternal-to-zygotic transition (MZT) is one of the most profound and orchestrated processes during the early life of embryos, yet factors that shape the temporal pattern of vertebrate MZT are largely unknown. We proposed the rapid clearance of mRNA during MZT may be facilitated by m6A and performed high throughput sequencing to study the m6A pattern and transcriptome dynamics during zebrafish embryogenesis. Our results showed that over one-third of zebrafish maternal mRNA can be marked by m6A, and the clearance of these maternal mRNAs is facilitated by an m6A reader protein, Ythdf2. Removal of Ythdf2 in zebrafish embryos decelerates the decay of m6A-modified maternal mRNAs and impedes zygotic genome activation. These embryos fail to initiate timely MZT, undergo cell cycle pause, and remain developmentally delayed throughout larval life. Additionally, injecting m6A reporter mRNA into individual embryos also revealed the potential involvement of m6A in single cell variation of gene expression among the differentiating cells. Our study reveals m6A-dependent RNA decay as a previously unidentified maternally driven mechanism that regulates maternal mRNA clearance during zebrafish MZT, highlighting the critical role of m6A mRNA methylation in transcriptome switching and animal development.