Affiliation:
1. Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724
Abstract
Position-effect variegation (PEV) results from the juxtaposition of euchromatic and heterochromatic components of eukaryotic genomes, silencing genes near the new euchromatin/heterochromatin junctions. Silencing is itself heritable through S phase, giving rise to distinctive random patterns of cell clones expressing the genes intermixed with clones in which the genes are silenced. Much of what we know about epigenetic inheritance in the soma stems from work on PEV aimed at identifying the components of the silencing machinery and its mechanism of inheritance. The roles of two central gene activities—the
Su
(
var
)
3-9
–encoded histone H3–lysine-9 methyltransferase and the
Su
(
var
)
205
-encoded methyl-H3–lysine-9 binding protein heterochromatin protein 1 (HP1a)—have been inferred from terminal phenotypes, leaving considerable gaps in understanding of how PEV behaves through development. Here, we investigate the PEV phenotypes of
Su
(
var
)
3-9
and
Su
(
var
)
205
mutations in live developing tissues. We discovered that mutation in
Su
(
var
)
205
compromises the initial establishment of PEV in early embryogenesis. Later gains of heterochromatin-induced gene silencing are possible but are unstable and lost rapidly. In contrast, a strain with mutation in
Su
(
var
)
3-9
exhibits robust silencing early in development but fails to maintain it through subsequent cell divisions. Our analyses show that, while the terminal phenotypes of these mutations may appear identical, they have arrived at them through different developmental trajectories. We discuss how our findings expand and clarify existing models for epigenetic inheritance of heterochromatin-induced gene silencing.
Funder
HHS | National Institutes of Health
Publisher
Proceedings of the National Academy of Sciences