The potential for early embryonic events to impact on adult physiology remains an important question in health and development. Using the Zdbf2 locus, Deborah Bourc’his team – Epigenetic Decisions and Reproduction – recently demonstrated that chromatin changes that occur in the pluripotent embryo can be dispensable for embryogenesis, but instead signal essential regulatory information to ensure full growth potential in the adult.
In mammals, early development is characterized by drastic transcriptional and chromatin changes immediately following fertilization. These are known to have direct roles in the embryo: erasure of the identity inherited from the parental gametes, acquisition of pluripotency and differentiation into various cellular functions. One outstanding question has been whether some of these early transcriptional/chromatin events might serve as programmers of later phenotypic and physiological traits.
Theoretically, early programming of gene expression requires an epigenetic switch: a regulatory element acquires a chromatin status in the early embryo, but this will be read out only later, after being stably maintained throughout development. Cytosine methylation represents a possible mediator of early programming of adult phenotypes, as the mark stably propagates across indefinite cell divisions.
We previously characterized the unusual regulation of the imprinted Zdbf2 locus (The Gpr1/Zdbf2 locus provides new paradigms for transient and dynamic genomic imprinting in mammals / Duffié R., Ajjan S., Greenberg M.V., Zamudio N., Escamilla del Arenal M., Iranzo J., Okamoto I., Barbaux S., Fauque P. and Bourc’his D. (2014) / Genes & Dev 28, 463-478), which is conserved between mice and humans: several features prompted us to consider it as an advantageous model to study this question. At this locus, the Long-isoform-of-Zdbf2 (Liz) gene is expressed only in the pluripotent embryo, during the first week of development after fertilization, before being definitely shut down prior to tissue specification. By using in cellula and in vivo genetic approaches in the mouse, we found that the very brief expression of Liz is required for operating a long-lasting epigenetic switch : it promotes de novo DNA methylation upstream of the Zdbf2 promoter, which itself evicts a repressive block of polycomb-deposited H3K27me3 marks. Importantly, failure to express Liz in the early embryo is not detrimental for the embryo itself, but has an impact later, on body physiology. Liz-deficient embryos develop normally, are healthy and fertile but show a reduced growth rate after birth. This culminates with a 20% body weight reduction at two weeks of age and persists throughout life. Indeed, without Liz, Zdbf2 is not released from polycomb represssion and fails to activate in the hypothalamus-pituitary axis postnatally. We therefore provide here a striking example of transcription-induced, early epigenetic programming of a locus, which has a major impact on the expression fate of a growth-promoting gene in post-natal life. Given that Liz functions as an epigenetic programmer within the first days of development, genetic and environmental perturbations of Liz expression in gametes and early embryos could predispose variable growth potential.
Transient transcription in the early embryo sets an epigenetic state that programs postnatal growth
Maxim V C Greenberg, Juliane Glaser, Máté Borsos, Fatima El Marjou, Marius Walter, Aurélie Teissandier, Déborah Bourc’his
Image: © Raquel Perez Palacios / Adult growth potential is programmed very early during development, when the embryo contains only a few cells.