Mechanisms for the inheritance of chromatin states

Studies in eukaryotes ranging from yeast to mammals indicate that specific chromatin structures can be inherited following DNA replication via mechanisms acting in cis. Both the initial establishment of such chromatin structures and their inheritance require sequence-dependent specificity factors and changes in histone posttranslational modifications. Here I propose models for the maintenance of epigenetic information in which DNA silencers or nascent RNA scaffolds act as sensors that work cooperatively with parentally inherited histones to re-establish chromatin states following DNA replication.     

In and out: histone variant exchange in chromatin

Alterations in nucleosome structure affect the accessibility of the DNA and can generate specialized domains of chromatin in the genome. Such changes can be introduced by posttranslational modifications of histones, by chromatin remodeling, or by the incorporation of variants of H2A and H3 into nucleosomes. In contrast to the canonical histones, which are deposited behind the replication fork during S phase, histone variants are incorporated in a process that is independent of DNA replication. Recent studies have shown that distinct multiprotein complexes are responsible for the targeted deposition of histone variants at active genes, centromeres and silent loci. The incorporation of histone variants most probably has epigenetic consequences and contributes to architectural changes in chromosomes.     

Variations on the topic of the "histone code"

Histones are the fundamental structural proteins intimately associated with eukaryotic DNA to form a highly ordered and condensed nucleoproteic complex termed chromatin. They are the targets of various posttranslational modifications including acetylation, methylation, phosphorylation and ubiquitination that modulate the structure/function of chromatin. The combinatorial nature of histone modifications is hypothesized to define a "histone code" that considerably extends the information potential of the genetic code, giving rise to epigenetic information. Moreover, most core histones consist of several nonallelic variants that can mark specific loci and could play an important role in establishment and maintenance of epigenetic memory. Here we will briefly present our current knowledge about histone posttranslational modifications and their implications in the regulation of epigenetic information. We will next describe core histone variants, insisting on their mode of incorporation into chromatin to discuss their epigenetic function and inheritance.     

Many players, one goal: how chromatin states are inherited during cell division.

Replication of genomic material is a process that requires not only high fidelity in the duplication of DNA sequences but also inheritance of the chromatin states. In the last few years enormous effort has been put into elucidating the mechanisms involved in the correct propagation of chromatin states. From all these studies it emerges that an epigenetic network is at the base of this process. A coordinated interplay between histone modifications and histone variants, DNA methylation, RNA components, ATP-dependent chromatin remodeling, and histone-specific assembly factors regulates establishment of the replication timing program, initiation of replication, and propagation of chromatin domains. The aim of this review is to examine, in light of recent findings, how so many players can be coordinated with each other to achieve the same goal, a correct inheritance of the chromatin state.     

A chemical field guide to histone nonenzymatic modifications

Histone nonenzymatic covalent modifications (NECMs) have recently emerged as an understudied class of posttranslational modifications that regulate chromatin structure and function. These NECMs alter the surface topology of histone proteins, their interactions with DNA and chromatin regulators, as well as compete for modification sites with enzymatic posttranslational modifications. NECM formation depends on the chemical compatibility between a reactive molecule and its target site, in addition to their relative stoichiometries. Here we survey the chemical reactions and conditions that govern the addition of NECMs onto histones as a manual to guide the identification of new physiologically relevant chemical adducts. Characterizing NECMs on chromatin is critical to attain a comprehensive understanding of this new chapter of the so-called “histone code”.     

Inheritance of epigenetic chromatin silencing

Maintenance of alternative chromatin states through cell divisions pose some fundamental constraints on the dynamics of histone modifications. In this paper, we study the systems biology of epigenetic inheritance by defining and analyzing general classes of mathematical models. We discuss how the number of modification states involved plays an essential role in the stability of epigenetic states. In addition, DNA duplication and the consequent dilution of marked histones act as a large perturbation for a stable state of histone modifications. The requirement that this large perturbation falls into the basin of attraction of the original state sometimes leads to additional constraints on effective models. Two such models, inspired by two different biological systems, are compared in their fulfilling the requirements of multistability and of recovery after DNA duplication. We conclude that in the presence of multiple histone modifications that characterize alternative epigenetic stable states, these requirements are more easily fulfilled.     

Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones

A central component of the epigenome is the pattern of histone post-translational modifications that play a critical role in the formation of specific chromatin states. Following DNA replication, nascent chromatin is a 1:1 mixture of parental and newly synthesized histones and the transfer of modification patterns from parental histones to new histones is a fundamental step in epigenetic inheritance. Here we report that loss of HAT1, which acetylates lysines 5 and 12 of newly synthesized histone H4 during replication-coupled chromatin assembly, results in the loss of accessibility of large domains of heterochromatin, termed HAT1-dependent Accessibility Domains (HADs). HADs are mega base-scale domains that comprise ∼10% of the mouse genome. HAT1 globally represses H3 K9 me3 levels and HADs correspond to the regions of the genome that display HAT1-dependent increases in H3 K9me3 peak density. HADs display a high degree of overlap with a subset of Lamin-Associated Domains (LADs). HAT1 is required to maintain nuclear structure and integrity. These results indicate that HAT1 and the acetylation of newly synthesized histones may be critical regulators of the epigenetic inheritance of heterochromatin and suggest a new mechanism for the epigenetic regulation of nuclear lamina-heterochromatin interactions.     

Posttranslational modifications of repair factors and histones in the cellular response to stalled replication forks

DNA damage during replication requires an integration of checkpoint response with replication itself and distinct repair pathways, such as replication pausing, recombination and translesion synthesis. Here we focus on recent advances in our understanding of how protein posttranslational modifications contribute to the maintenance of fork integrity. In particular, we examine the role of histone modifications and chromatin remodeling complexes in this process.