Inheritance of Histone (H3/H4): A Binary Choice?

Parental histones can be inherited close to their starting DNA sequence (i.e., with positional memory).Histone chaperone activities intrinsic to the replisome may mediate positional memory.A binary choice may be made for each (H3/H4)2 between recycling through a soluble pool and redeposition with positional memory. Histones carry information in the form of post-translational modifications (PTMs). For this information to be propagated through cell cycles, parental histones and their PTMs need to be maintained at the same genomic locations. Yet, during DNA replication, every nucleosome in the genome is disrupted to allow passage of the replisome. Recent data have identified histone chaperone activities that are intrinsic components of the replisome and implicate them in maintaining parental histones during DNA replication. We propose that structural and kinetic coordination between DNA replication and replisome-associated histone chaperone activities ensures positional inheritance of histones and their PTMs. When this coordination is perturbed, histones may instead be recycled to random genomic locations by alternative histone chaperones. Histones carry information in the form of post-translational modifications (PTMs). For this information to be propagated through cell cycles, parental histones and their PTMs need to be maintained at the same genomic locations. Yet, during DNA replication, every nucleosome in the genome is disrupted to allow passage of the replisome. Recent data have identified histone chaperone activities that are intrinsic components of the replisome and implicate them in maintaining parental histones during DNA replication. We propose that structural and kinetic coordination between DNA replication and replisome-associated histone chaperone activities ensures positional inheritance of histones and their PTMs. When this coordination is perturbed, histones may instead be recycled to random genomic locations by alternative histone chaperones. A well-accepted although largely untested hypothesis is that histone PTMs serve as epigenetic information to regulate gene expression. The information content of histone PTMs depends on their placement at specific genomic locations. For this information to be heritable, the linkage between DNA sequence and modifications must be preserved. Yet, during DNA replication, every nucleosome in the genome is disrupted, and the number of nucleosomes is doubled. Thus, if histone modifications carry epigenetic information, there must be mechanisms to maintain them at specific genomic locations, which we refer to as histone inheritance, and the precision of these mechanisms constrains the memory capacity of histone PTMs (Figure 1, paths 1 and 2). Parental histones can also be recycled through a soluble pool and deposited randomly on nascent DNA (Figure 1, path 3). Recent work has identified histone chaperones that act at DNA replication forks, including those that are part of the DNA replication machinery itself, and described the inheritance patterns of parental histones on the genome. We summarize this work and use it to propose a model for how the fate of parental histones is controlled. A prerequisite for histones to carry information through DNA replication is that parental histones are assembled on newly replicated DNA with their PTMs. Rapid assembly of parental histones was established in the 1970s and confirmed in subsequent decades (see [1.Annunziato A.T. Assembling chromatin: the long and winding road.Biochim. Biophys. Acta. 2013; 1819: 196-210Crossref PubMed Scopus (56) Google Scholar] for a comprehensive review), while more recent work confirms that, in most cases analyzed, parental PTMs are preserved through DNA replication [2.Alabert C. et al.Two distinct modes for propagation of histone PTMs across the cell cycle.Genes Dev. 2015; 29: 585-590Crossref PubMed Scopus (219) Google Scholar,3.Benson L.J. et al.Modifications of H3 and H4 during chromatin replication, nucleosome assembly, and histone exchange.J. Biol. 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