EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

Abstract

The first mammalian cell lineage commitment is the formation of the trophectoderm (TE) and the inner cell mass (ICM) lineages during preimplantation development. Proper development of the TE and ICM lineages is dependent upon establishment of specific transcriptional programs. However, the epigenetic mechanisms that functionally contribute to establish TE- and ICM-specific transcriptional programs are poorly understood. Here, we show that proper development of the TE and ICM lineages is coordinated via combinatorial regulation of embryonic ectoderm development (EED) and lysine-specific demethylase 6B (KDM6B). During blastocyst formation, the relative levels of EED and KDM6B expression determine altered polycomb repressor 2 (PRC2) complex recruitment and incorporation of the repressive histone H3 lysine 27 trimethylation (H3K27Me3) mark at the chromatin domains of TE-specific master regulators CDX2 and GATA3, leading to their activation in the TE lineage and repression in the ICM lineage. Furthermore, ectopic gain of EED along with depletion of KDM6B in preimplantation mouse embryos abrogates CDX2 and GATA3 expression in the nascent TE lineage. The loss of CDX2 and GATA3 in the nascent TE lineage results in improper TE development, leading to failure in embryo implantation to the uterus. Our study delineates a novel epigenetic mechanism that orchestrates proper development of the first mammalian cell lineages.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00069-13.

ACKNOWLEDGMENTS

We thank Terry Magnuson for providing the Eed^−/− mESCs, Thaddeus G. Golos for providing monkey blastocysts, Michael J. Soares for important suggestions, and Partho Chattoraj for experimental help.

The work is supported by NIH grants HD062546, HL104322, and HL106311 to S. Paul. B. Saha is supported by a Biomedical Research Training Program postdoctoral fellowship, and P. Home is supported by an American Heart Association postdoctoral fellowship.

All work with human embryos was done with private funding and without any support (including support for instruments, facilities, reagents, or personnel) from federal funding.