Antonio Giraldez, PhD
Fergus F. Wallace Professor of Genetics, Chair of Genetics Department
Department of Genetics
Yale School of Medicine
(March 6, 2018)
Deciphering the Regulatory Codes Shaping the Maternal to Zygotic Transition During Development
There are still many open questions about the genetics of early embryo development. Much depends on maternal RNA and its control over gene expression. The instructions provided by the RNA are a basic component of development. In his seminar, Doctor Giraldez discussed his work exploring what factors promote stability and what factors destabilize maternal RNA, and what proteins are involved in the transition from maternal RNA to embryo.
Post-transcriptional regulation plays a fundamental role in shaping gene expression after fertilization across animals, a period where the embryo is acquiring totipotency. To understand the post-transcriptional regulatory code that shapes mRNA decay and translation regulation during this maternal to zygotic transition his lab combined three approaches: i) RESA, a novel RNA Element Selection Assay which quantifies the regulatory activity of sequences in the 3’UTR and the CDS throughout the transcriptome in vivo. ii) Interactome capture, to identify the proteins involved and iii) Parallel iClip for 30 RNA binding proteins to define their regulatory targets and motifs during development.
These approaches have provided three major insights into the regulatory landscape during embryogenesis. First, they determined that individual codons shape mRNA stability through deadenylation, an effect that is conserved from Drosophila to mammals during the maternal-to-zygotic transition. Second, they have identified common regulatory sequences in the 3’UTR and the CDS that have antagonistic effects in mRNA stability. They find that overall, 3’UTR regions confer stability, with the most prominent exception of miRNA target sites. In contrast, coding sequences confer destabilization. They showed that sequence bias composition explains part of this regulation, but in addition, identified motifs that are associated with increased and decreased stability of the mRNA in vivo. Finally, to define the set of regulatory proteins in vivo, they have undertaken interactome capture identifying 170 proteins that are associated with mRNAs during this transition. Parallel iClip analysis for 30 of these proteins revealed a binding map and their regulatory motifs in vivo. Comparing the iClip analysis with the identification of regulatory motifs in vivo revealed a combinatorial code that mediate mRNA stability and decay during the maternal to zygotic transition.