Abstract
Heterochromatic gene silencing is an important form of gene regulation that usually requires specific histone modifications. A popular model posits that inheritance of modified histones, especially in the form of H3-H4 tetramers, underlies inheritance of heterochromatin. Because H3-H4 tetramers are randomly distributed between daughter chromatids during DNA replication, rare occurrences of asymmetric tetramer inheritance within a heterochromatic domain would have the potential to destabilize heterochromatin. This model makes a prediction that shorter heterochromatic domains would experience unbalanced tetramer inheritance more frequently, and thereby be less stable. In contrast to this prediction, we found that shortening a heterochromatic domain in Saccharomyces had no impact on the strength of silencing nor its heritability. Additionally, we found that replisome mutations that disrupt inheritance of H3-H4 tetramers had only minor effects on heterochromatin stability. These findings suggest that histones carry little or no memory of the heterochromatin state through DNA replication.
Highlights
A central question in biology is how cells with identical genotypes can exhibit different, heritable phenotypes
This study addresses three questions regarding the inheritance of heterochromatin in Saccharomyces: 1) Does the size of a silenced domain determine the fidelity of inheritance? 2) Does removal of Sir1, a protein that facilitates recruitment of silencing machinery to silencers, uncover an effect of chromatin domain size on heritability of transcriptional states? 3) Do replisome components that facilitate symmetric inheritance of parental H3-H4 tetramers promote inheritance of transcriptional states?
If parental H3-H4 tetramers were randomly partitioned between the two daughter chromatids during replication, one would expect a chromatin state to be lost if, by chance, one of the daughter chromatids failed to receive enough parental H3H4 tetramers to support the propagation of that state
Summary
A central question in biology is how cells with identical genotypes can exhibit different, heritable phenotypes. By definition, these phenotypes are determined by information that is epigenetic, or ‘above the genome.’. Just as genetic inheritance requires faithful replication of DNA, epigenetic inheritance requires replication of information that is transmitted to both daughter cells during division. Faithful transmission of epigenetic information is crucial for multiple heterochromatin-based processes such as X-chromosome inactivation in mammals and cold-induced gene silencing in Arabidopsis. In these cases and others, the epigenetic inheritance of heterochromatin indicates that some components of heterochromatin behave as heritable units. The identity of this epigenetic information remains unclear and heavily debated
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