Establishment of epigenetic patterns in development

Abstract

The distinct cell types of the body are established from the fertilized egg in development and assembled into functional tissues. Functional characteristics and gene expression patterns are then faithfully maintained in somatic cell lineages over a lifetime. On the molecular level, transcription factors initiate lineage-specific gene expression programmmes and epigenetic regulation contributes to stabilization of expression patterns. Epigenetic mechanisms are essential for maintaining stable cell identities and their disruption can lead to disease or cellular transformation. Here, we discuss the role of epigenetic regulation in the early mouse embryo, which presents a relatively well-understood system. A number of studies have contributed to the understanding of the function of Polycomb group complexes and the DNA methylation system. The role of many other chromatin regulators in development remains largely unexplored. Albeit the current picture remains incomplete, the view emerges that multiple epigenetic mechanisms cooperate for repressing critical developmental regulators. Some chromatin modifications appear to act in parallel and others might repress the same gene at a different stage of cell differentiation. Studies in pluripotent mouse embryonic stem cells show that epigenetic mechanisms function to repress lineage specific gene expression and prevent extraembryonic differentiation. Insights into this epigenetic "memory" of the first lineage decisions help to provide a better understanding of the function of epigenetic regulation in adult stem cell differentiation.

Fig. 1

Epigenetic regulation in early mouse development. a Schematic representation of mouse development is aligned with key epigenetic events in panels b and c. The trophectoderm (TE) lineage is the first to differentiate from cells that have an outside position of morula stage embryos (red shading). At the blastocyst stage, the hypoblast (green) is specified. Inner cell mass cells (yellow) will give rise to the developing mouse embryo whereas TE and hypoblast form extraembryonic tissues. b Genomic imprints are parent-of-origin-specific marks that are maintained during embryogenesis and regulate the differential expression of the maternal and paternal copy of imprinted genes. X chromosome inactivation and reactivation is observed during development of female embryos. c A diagram illustrating global changes in DNA methylation (5mC) and DNA hydroxymethylation (5hmC) levels. In cleavage stage embryos the paternal (blue lines) and maternal (red) genomes are differentially marked by 5hmC and 5mC, respectively. Both 5mC and 5hmC levels decrease during development to the blastocyst stage and then 5mC increases as the embryonic lineages are formed

Fig. 2

Transcriptional control and epigenetic regulation in the lineages of the mouse blastocyst. a The three lineages of the blastocyst can give rise to stem cell lines in culture. Transcription factor networks as observed in trophectoderm stem (TS) cells, extraembryonic endoderm stem (XEN) cells and ES cells are shown (green) and their mutual antagonistic regulation is indicated. b Repression of key transcription factors of extraembryonic lineage development in ES cells has been analysed. A number of epigenetic regulators contribute to repress genes and their activity and interactions with chromatin on gene promoters are summarized in the scheme

Fig. 3

Transcription factors, chromatin-modifying complexes and lincRNAs have been implicated in specifying epigenetic patterns. Transcription factors (TFs) activate genes in a cell-type- or lineage-specific manner. In addition TFs also associate with chromatin- or DNA-modifying activities that repress certain of their target genes. Among TF-activated genes are a class of long noncoding RNAs (LincRNAs) that can bind different chromatin regulators and might function to target them to certain genomic regions. Thereby, lincRNAs provide a mechanism for establishing epigenetic patterns on regions that do not have binding sites for TFs. Repressive chromatin marks are important for preventing activation of genes associated with other lineages thereby preventing aberrant differentiation