Fig. 1.

SSIS hypothesis and Liu et al. (2002) experiment. a The SSIS hypothesis predicts that asymmetrically dividing stem cells epigenetically differentiate sister chromatids during S-phase. This is followed by asymmetric sister chromatid segregation to daughter cells. Here, older W-template-strand containing sister chromatids are segregated to one sister cell, and older C-template-strand containing sister chromatids are segregated to the other sister cell, to constitute a DNA-based mechanism of asymmetric cell division. b Outline of Liu et al.’s (2002) experiment (black). 5′ (“hp”) and 3′ (“rt”) parts of the selectable hprt minigene, flanked by a single loxP site (triangle) are placed in identical genomic positions on homologous chromosomes (line with filled circle on top as centromere). Centro-mere distal to the loxP site is a heterozygous marker (M on the “paternal” homolog and m on the “maternal” homolog). Cre recombination restores the hprt minigene and confers HAT resistance (HAT^R). Please note that after recombination, only centromere-proximal areas maintain their original Ma and Pa identities. When Cre recombination happens in G2, recombined products can either segregate together (Z segregation) or away (X segregation) from each other. Z and G1 recombination do not change the original heterozygous (M/m) marker. X segregation leads to homozygosis (m/m HAT^R cells). DT1E9 ESCs, where the hprt-loxP cassettes were placed centromere-proximal on chr. 7 always undergo X segregation. An explanation for this was previously provided by us and indicated in red. During G2 recombination, only old W-strand- and old C-strand-containing sister chromatids are allowed to recombine. This is followed by selective WW:CC segregation in mitosis, giving rise to homozygosed (m/m) HAT^R cells only