Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Fernando H. Biase (1) , Chanaka Rabel (2) , Michel Guillomot (3, 4) , Isabelle Hue (3, 4) , Kalista Andropolis (2) , Colleen A. Olmstead (2) , Rosane Oliveira (2) , Richard Wallace (2) , Daniel Le Bourhis (3, 4) , Christophe Richard (3, 5, 4) , Evelyne Campion (3, 4) , Aurélie Chaulot-Talmon (3, 4) , Corinne Giraud-Delville (3, 4) , Geraldine Taghouti (3, 4) , Hélène Jammes (3, 4) , Jean-Paul Renard (3, 4) , Olivier Sandra (3, 4) , Harris A. Lewin (1, 2, 6)

1 Institute for Genomic Biology
2 Department of Animal Sciences
3 BDR - Biologie du Développement et Reproduction
4 Université Paris-Saclay
5 UE 1298 Unité Commune d'Expérimentation Animale
6 Department of Evolution and Ecology and the Genome Center

A major unresolved issue in the cloning of mammals by somatic cell nuclear transfer (SCNT) is the mechanism by which the process fails after embryos are transferred to the uterus of recipients before or during the implantation window. We investigated this problem by using RNA sequencing (RNA-seq) to compare the transcriptomes in cattle conceptuses produced by SCNT and artificial insemination (AI) at day (d) 18 (preimplantation) and d 34 (postimplantation) of gestation. In addition, endometrium was profiled to identify the communication pathways that might be affected by the presence of a cloned conceptus, ultimately leading to mortality before or during the implantation window. At d 18, the effects on the transcriptome associated with SCNT were massive, involving more than 5,000 differentially expressed genes (DEGs). Among them are 121 genes that have embryonic lethal phenotypes in mice, cause defects in trophoblast and placental development, and/or affect conceptus survival in mice. In endometria at d 18, <0.4% of expressed genes were affected by the presence of a cloned conceptus, whereas at d 34, ∼36% and <0.7% of genes were differentially expressed in intercaruncular and caruncular tissues, respectively. Functional analysis of DEGs in placental and endometrial tissues suggests a major disruption of signaling between the cloned conceptus and the endometrium, particularly the intercaruncular tissue. Our results support a "bottleneck" model for cloned conceptus survival during the periimplantation period determined by gene expression levels in extraembryonic tissues and the endometrial response to altered signaling from clones.

Mots clés: somatic cell nuclear transfer; conceptus; placentation; conceptus maternal communication; chorion; cell signalling; cloning; endometrium; genes

Mots clés: placenta; signalisation cellulaire; clonage; endomètre; gène

Domaines: Biologie du développement; Embryologie et organogenèse

Fernando H. Biase, Chanaka Rabel, Michel Guillomot, Isabelle Hue, Kalista Andropolis, et al.. Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (51), pp.14492-14501. ⟨10.1073/pnas.1520945114⟩. ⟨hal-01602490⟩