Question

Describe how chromatin structure can be inherited and how this might be important biologically.

Answer 1

Histone Modification-Based Chromatin Inheritance

Current models of chromatin inheritance are based on experimental evidence on the fate of nucleosomal histones following DNA replication. Studies using pulse-chase experiments followed by fractionation to measure chromatin-bound histones strongly suggest that at the bulk level parental histones H3 and H4 do not exchange with newly synthesized H3 and H4 but remain bound to the newly replicated daughter DNA strands (Jackson and Chalkley, 1974) . These studies and electron microscope images of replicating chromatin further suggest that during DNA replication parental histones are distributed randomly between the two daughter DNA strands (Jackson and Chalkley, 1985; Sogo et al., 1986). More recently, genome-wide studies in budding yeast using an epitope tag exchange strategy that allows parental histones to be distinguished from newly synthesized ones have defined the patterns of parental histone inheritance, demonstrating histone retention at a gene-specific level (Radman-Livaja et al., 2011). Together with extensive evidence on the role of histone posttranslational modifications in the regulation of transcription, these studies have given rise to the proposal that histone modifications can be re-established by complexes that recognize a specific modification on an inherited parental histone and catalyze the same type of modification on adjacent newly deposited nucleosomes (Dodd et al., 2007; Grewal and Moazed, 2003; Kaufman and Rando, 2010; Kouzarides, 2007; Rusche et al., 2003; Strahl and Allis, 2000; Suganuma and Workman, 2008) (Figure 1). With some important differences (discussed later), this model is similar to how the maintenance DNA methyltransferase, Dnmt1, is thought to re-establish DNA methylation patterns by preferentially associating with and methylating hemimethylated DNA (Holliday, 1987; Schaefer et al., 2007). The model requires that histone modifications provide sufficient specificity to directly or indirectly recruit cognate-modifying enzymes and that the kinetics of their erasure is slower than the kinetics of postreplication re-establishment. Although in principle this mechanism based entirely on histones could account for the epigenetic inheritance of chromatin states, experiments in yeast and flies, discussed below, suggest that histone modifications alone are not sufficient for epigenetic inheritance.

Storage of eukaryotic DNA in small, compact nuclei requires that this DNA be tightly coiled and compacted in the form of chromatin. However, the structure of chromatin also appears to serve a second, possibly more important role, in that it gives eukaryotic cells the capability to exert complex levels of control over gene expression.

As described throughout this article, chromatin and the DNA sequences it contains are constantly undergoing modifications, thereby periodically exposing different regions of DNA to transcription factors and RNA polymerases. The cumulative effects of these changes are various states of transcriptional control and the ability of eukaryotic cells to turn genes on and off as needed. This complexity provides eukaryotes with a means of making the most of a relatively small number of genes. However, much research remains to be performed before investigators precisely understand how the many mechanisms of chromatin remodeling operate, as well as how they work together to result in the complex patterns of gene expression characteristic of eukaryotic cells.