Developmental biology

Marked from the start

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Not all cells in the early mammalian embryo are created equal. Even at the four-cell stage, embryonic cells that follow a particular pattern of division already have their developmental fate assigned to them. No cell will contribute exclusively to a specific cell type in the later embryo. But the progeny of some cells make a greater contribution to the 'inner cell mass' — the stem cells destined to become the fetus — and its surrounding 'trophectoderm', which forms extraembryonic structures such as the placenta. The progeny of other cells will make a greater contribution to other extraembryonic structures.

Reporting on page 214 of this issue, Maria-Elena Torres-Padilla and colleagues find that the key to the cells' destiny lies, at least in part, outside their genes (M.-E. Torres-Padilla et al. Nature 445, 214–218; (2007).

To fit into the nucleus, DNA is wound around histone proteins. Both the DNA and the histones can be studded with a variety of additional chemical groups — notably, methyl groups — that affect how tightly the structure is packed. These 'epigenetic marks' determine how accessible the genes in certain regions are, and they can interact directly with gene regulatory factors to activate or silence nearby genes.

Specific patterns of these marks are associated with particular cell fates in later stages of development, and with allowing stem cells to maintain the ability to develop into many different cell types (pluripotency). So Torres-Padilla et al. speculated that epigenetic instructions might also help to determine the fate of early embryonic cells.

The authors concentrated on an epigenetic mark related to gene activation — methylation of an arginine amino acid in the histone H3 protein. They looked for differences between the cells destined for different fates in mouse embryos. An embryo is pictured here at the 32-cell stage, with the inner cell mass shown in red and the two types of trophectoderm, polar and mural, shown in blue and green respectively.

Credit: D.-E. PARFITT & M. ZERNICKA-GOETZ

In the four-cell embryo, methylation of H3 was highest in cells that were due to become the inner cell mass and polar trophectoderm, and lowest in cells destined to contribute to the mural trophectoderm. To see whether this epigenetic mark really affected developmental fate, the authors manipulated the cells to overexpress the enzyme that carries out arginine methylation in two-cell embryos. This caused all the cells' progeny to become part of the inner cell mass — and increased the expression of certain proteins associated with pluripotency.

Epigenetic marks thus seem to be among the first developmental instructions that the embryonic cell receives.

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