Histones help clones forget their pasts

Amid the hype surrounding cloning by somatic cell nuclear transfer, the astonishingly low success rate of the process has received relatively little attention. Now, on page 37, Kim et al. show that histone deacetylation is an important feature of the nuclear reprogramming that occurs in oocytes, both during normal meiosis and in nuclear transfer experiments. The work suggests strategies that could improve the efficiency of cloning, and also helps to explain how somatic cells retain their identities during mitosis.

Using immunocytochemistry, the authors examined changes in histone acetylation in oocytes during meiosis, and compared these with mitotic acetylation patterns. In meiotic oocytes, histone acetylation levels drop markedly. A similar decrease occurs in somatic cell nuclei that are transferred into enucleated oocytes. During mitosis, however, the same sites on histones remain acetylated. The histone deacetylase enzyme HDAC1 colocalizes with chromosomes during meiosis, but not during mitosis.

Kim et al. suggest that the acetylation states of histones propagate “cell memory,” ensuring that cells retain information about their lineages during mitosis. In meiotic oocytes or transferred somatic cell nuclei, histone deacetylases gain access to the chromosomes, erasing cell memory and reprogramming the nucleus so that it can give rise to all of the cell types in a new embryo.

Currently, the only way to determine whether a transferred somatic cell nucleus has been reprogrammed in a cloning experiment is to implant the oocyte and wait for the embryo to develop. The new work suggests that an assay of histone acetylation levels might sort the reprogrammed nuclei from the failures, potentially increasing the efficiency of cloning. Reagents that increase deacetylation or target histone deacetylases to the chromosomes might also make the process more reliable. The authors are now trying to identify the molecular mechanisms that regulate the localization of histone deacetylases during meiosis. ▪