Abstract
Author SummaryIt is widely believed that chromatin, the nucleoprotein packaged state of eukaryotic genomes, can carry epigenetic information and thus transmit gene expression patterns to replicating cells. However, the inheritance of genomic packaging status is subject to mechanistic challenges that do not confront the inheritance of genomic DNA sequence. Most notably, histone proteins must at least transiently dissociate from the maternal genome during replication, and it is unknown whether or not maternal proteins re-associate with daughter genomes near the sequence they originally occupied on the maternal genome. Here, we use a novel method for tracking old proteins to determine where histone proteins accumulate after 1, 3, or 6 generations of growth in yeast. To our surprise, ancestral histones accumulate near the 5′ end of long, relatively inactive genes. Using a mathematical model, we show that our results can be explained by the combined effects of histone replacement, histone movement along genes from 3′ towards 5′ ends, and histone spreading during replication. Our results show that old histones do move but stay relatively close to their original location (within around 400 base-pairs), which places important constraints on how chromatin could potentially carry epigenetic information. Our findings also suggest that accumulation of the ancestral histones that are inherited can influence histone modification patterns.
Highlights
In addition to the information encoded in DNA sequence, replicating cells can inherit epigenetic information, which refers to variable phenotypes that are heritable without an underlying change in DNA sequence
It is widely believed that chromatin, the nucleoprotein packaged state of eukaryotic genomes, can carry epigenetic information and transmit gene expression patterns to replicating cells
Histone proteins must at least transiently dissociate from the maternal genome during replication, and it is unknown whether or not maternal proteins re-associate with daughter genomes near the sequence they originally occupied on the maternal genome
Summary
In addition to the information encoded in DNA sequence, replicating cells can inherit epigenetic information, which refers to variable phenotypes that are heritable without an underlying change in DNA sequence. The idea that chromatin structure carries epigenetic information poses a central mechanistic question—since chromosome replication involves dramatic perturbations to chromatin structure ranging from old histone displacement to widespread incorporation of newly synthesized histones, how can chromatin states be stably maintained? To understand the mechanism by which chromatin states could be inherited, it is necessary to understand the unique challenges posed by histone protein dynamics during replication [4,5,6,7]. Histones must at least transiently dissociate from the genome during passage of the replication fork—if old histones carrying epigenetic information do not re-associate with daughter genomes at the location from which they came, this could lead to ‘‘epimutation,’’ analogous to DNA bases moving relative to one another during genomic replication. How old histones influence new histones, the basis for positive feedback, can be considered analogous to asking what the equivalent of base-pairing is during chromatin replication
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