A mouse-specific retrotransposon drives a conserved Cdk2ap1 isoform essential for development

Retrotransposons mediate gene regulation in important developmental and pathological processes. Here, we characterized the transient retrotransposon induction during preimplantation development of eight mammals. Induced retrotransposons exhibit similar preimplantation profiles across species, confer...

Full description

Saved in:

Bibliographic Details
Published in:	Cell Vol. 184; no. 22; pp. 5541 - 5558.e22
Main Authors:	Modzelewski, Andrew J., Shao, Wanqing, Chen, Jingqi, Lee, Angus, Qi, Xin, Noon, Mackenzie, Tjokro, Kristy, Sales, Gabriele, Biton, Anne, Anand, Aparna, Speed, Terence P., Xuan, Zhenyu, Wang, Ting, Risso, Davide, He, Lin
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 28-10-2021
Subjects:	Animals Base Sequence Blastocyst - metabolism Cdk2 Cdk2ap1 Cell Proliferation Conserved Sequence Embryonic Development - genetics Evolution, Molecular Female Gene Expression Regulation, Developmental Human Embryonic Stem Cells - metabolism Humans implantation mammals Mammals - genetics Mice Mice, Inbred C57BL Mice, Knockout Models, Biological mouse preimplantation embryos Promoter Regions, Genetic promoters Protein Isoforms - metabolism Protein Kinases - metabolism Retroelements - genetics retrotransposons transposons Tumor Suppressor Proteins - metabolism mouse implantation preimplantation embryos mammals cell proliferation Cdk2 Cdk2ap1 transposons retrotransposons promoters
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Retrotransposons mediate gene regulation in important developmental and pathological processes. Here, we characterized the transient retrotransposon induction during preimplantation development of eight mammals. Induced retrotransposons exhibit similar preimplantation profiles across species, conferring gene regulatory activities, particularly through long terminal repeat (LTR) retrotransposon promoters. A mouse-specific MT2B2 retrotransposon promoter generates an N-terminally truncated Cdk2ap1ΔN that peaks in preimplantation embryos and promotes proliferation. In contrast, the canonical Cdk2ap1 peaks in mid-gestation and represses cell proliferation. This MT2B2 promoter, whose deletion abolishes Cdk2ap1ΔN production, reduces cell proliferation and impairs embryo implantation, is developmentally essential. Intriguingly, Cdk2ap1ΔN is evolutionarily conserved in sequence and function yet is driven by different promoters across mammals. The distinct preimplantation Cdk2ap1ΔN expression in each mammalian species correlates with the duration of its preimplantation development. Hence, species-specific transposon promoters can yield evolutionarily conserved, alternative protein isoforms, bestowing them with new functions and species-specific expression to govern essential biological divergence. [Display omitted] •Numerous retrotransposons act as preimplantation-specific gene regulatory elements•An MT2B2 retrotransposon promoter is essential for mouse preimplantation development•MT2B2-driven Cdk2ap1ΔN and canonical Cdk2ap1 exhibit isoform-specific functions•Retrotransposon promoters can yield conserved gene isoforms with unique regulation A transient retrotransposon induction in mammalian preimplantation embryos yields numerous gene regulatory events. Deletion of an MT2B2 retrotransposon promoter abolishes a Cdk2ap1 isoform (Cdk2ap1ΔN), impairing cell proliferation and causing embryonic lethality. Cdk2ap1ΔN is evolutionarily conserved, generated by species-specific promoters, including transposon-derived promoters, to yield divergent expression patterns.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally. A.J.M, D.R. and L.H. conceived the initial hypotheses. A.J.M. performed most mouse embryo experiments, W.S. and D.R. performed most bioinformatics analyses. A.L. performed oviduct transfer to generate edited mice. X.Q. and K.T. characterized implantation defects of Cdk2ap1 mutants, maintained mouse husbandry, and quantified Cdk2ap1 expression. W.S., D.R., T.W., J.C., A.B. and T.S. performed bioinformatics analyses to quantify retrotransposon expression and characterize retrotransposon:gene isoforms. M.N., G.S. and A.J.M. performed manual curation and bioinformatics analyses to determine the ORF alterations generated by retrotransposon:gene isoforms. A.A. constructed a website to host resources of our bioinformatic analyses. D.R. T.W. and L.H guided all bioinformatics analyses and experimental executions. A.J.M and W.S. generated most figures and tables. A.J.M, W.S. and L.H. drafted the manuscript, all others revised and proofread. Author contributions
ISSN:	0092-8674 1097-4172
DOI:	10.1016/j.cell.2021.09.021