Epigenetic mechanisms for primary differentiation in mammalian embryos

This review examines main developments related to the interface between primary mammalian cell differentiation and various aspects of chromosomal structure changes, such as heterochromatin dynamics, DNA methylation, mitotic recombination, and inter- and intrachromosomal differentiation. In particular, X chromosome difference, imprinting, chromosomal banding, methylation pattern, single-strand DNA breaks, sister chromatid exchanges (SCEs), and sister chromatid asymmetry are considered. A hypothesis is put forward which implies the existence of an epigenetic asymmetry versus mirror symmetry of sister chromatids for any DNA sequences. Such epigenetic asymmetry appears as a result of asymmetry of sister chromatid organization and of SCE and is a necessary (not sufficient) condition for creating cell diversity. The sister chromatid asymmetry arises as a result of consecutive rounds of active and passive demethylation which leads after chromatin assembly events to chromatid difference. Single-strand DNA breaks that emerge during demethylation trigger reparation machinery, provend as sister chromatid exchanges, which are not epigenetically neutral in this case. Taken together, chromatid asymmetry and SCE lead to cell diversity regarding their future fate. Such cells are considered pluripotent stem cells which after interplay between a set of chromosomal domains and certain substances localized within the cytoplasmic compartments (and possibly cell interactions) can cause sister cells to express different gene chains. A model is suggested that may be useful for stem cell technology and studies of carcinogenesis.