Heterochromatin remains condensed throughout the cell cycle, is generally transcriptionally inert and is built and maintainedbygroupsoffactors witheachgroupmember sharing a similar function. In mammals, these groups include sequence-specific transcriptional repressors, functionalRNAandproteinsinvolvedinDNAandhistone methylation. Heterochromatin is cemented together via interactions within and between each protein group and ismaintainedbythecell’sreplicationmachinery.Itcanbe constitutive (permanent) or facultative (developmentally regulated) and be any size, from a gene promotor to a whole genome. By studying the formation of facultative heterochromatin, we have gained information about how heterochromatin (...) is assembled. We have discovered that there are many different architectural plans for the building of heterochromatin, leading to a seemingly never-ending variety of heterochromatic loci, with each built according to a general rule. (shrink)

We focus here on the intercalary heterochromatin (IH) of Drosophila melanogaster and, in particular, its molecular properties. In the polytene chromosomes of Drosophila, IH is represented by a reproducible set of dense bands scattered along the euchromatic arms. IH contains mainly unique DNA sequences, and shares certain features with other heterochromatin types such as pericentric, telomeric, and PEV‐induced heterochromatin, the inactive mammalian X‐chromosome and the heterochromatized male chromosome set in coccids. These features are transcriptional silencing, chromatin compactness, (...) late DNA replication, underrreplication or elimination in somatic cells, and formation of the heterochromatin state in early embryogenesis. Post‐translational modification of histones and the specific nonhistone protein complexes are shown to participate in the establishment and maintenance of silencing for all heterochromatin types. Many IH regions contain binding sites for HP1 and/or Pc‐G proteins and all the regions are sites of heterochromatin‐associated SuUR protein. Some IH regions are known to contain homeotic genes. Summarizing these data, we suggest that IH regions comprise stable inactivated genes, whose silencing is developmentally programmed. BioEssays 25:1040–1051, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The centromere is the region of the chromosome where the kinetochore forms. Kinetochores are the attachment sites for spindle microtubules that separate duplicated chromosomes in mitosis and meiosis. Kinetochore formation depends on a special chromatin structure containing the histone H3 variant CENP‐A. The epigenetic mechanisms that maintain CENP‐A chromatin throughout the cell cycle have been studied extensively but little is known about the mechanism that targets CENP‐A to naked centromeric DNA templates. In a recent report published in Science,1 such de (...) novo centromere assembly of CENP‐A is shown to be dependent on heterochromatin and the RNA interference pathway. BioEssays 30:526–529, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In eukaryotic cells, heterochromatin is typically composed of tandem DNA repeats and plays crucial roles in gene expression and genome stability. It has been reported that silencing at individual units within tandem heterochromatin repeats exhibits a position‐dependent variation. However, how the heterochromatin is organized at an individual repeat level remains poorly understood. Using a novel genetic approach, our recent study identified a conserved protein Rex1BD required for position‐dependent silencing within heterochromatin repeats. We further revealed that Rex1BD (...) interacts with the 14‐3‐3 protein to regulate heterochromatin silencing by linking RNAi and HDAC pathways. In this review, we discuss how Rex1BD and the 14‐3‐3 protein coordinate to modulate heterochromatin organization at the individual repeat level, and comment on the biological significance of the position‐dependent effect in heterochromatin repeats. We also identify the knowledge gaps that still need to be unveiled in the field. (shrink)

Heterochromatin protein 1 (HP1) is a positive regulator of active transcription in euchromatin. HP1 was first identified inDrosophila melanogasteras a major component of heterochromatin. Most eukaryotes have at least three isoforms of HP1, which are conserved in overall structure but localize differentially to heterochromatin and euchromatin. Although initial studies revealed a key role for HP1 in heterochromatin formation and gene silencing, recent progress has shed light on additional roles for HP1 in processes such as euchromatic gene (...) expression. Recent studies have highlighted the importance of HP1‐mediated gene regulation in euchromatin. Here, we focus on recent advances in understanding the role of HP1 in active transcription in euchromatin and how modification and localization of HP1 can regulate distinct functions for this protein in different contexts. (shrink)

DNA repetitions may provoke heterochromatinization. We explore here a model in which multiple cis‐acting sequences that display no silencing activity on their own (protosilencers) may cooperate to establish and maintain a heterochromatin domain efficiently. Protosilencers, first defined in budding yeast, have now been found in a wide range of genomes where they appear to stabilize and to extend the propagation of heterochromatin domains. Strikingly, isolated or moderately repeated protosilencers can also be found in promoters where they participate in (...) transcriptional activation and have insulation functions. This suggests that the proper juxtaposition of a threshold number of protosilencers converts them from neutral or transactivating elements into ones that nucleate heterochromatin. Interactions might be transient or permanent, and are likely to occur over distances by looping. This model provides a conceptual framework for as varied phenomena as telomere‐driven silencing in Drosophila, X inactivation in mammals, and rDNA silencing in S. cerevisiae. It may also account for the silencing that occurs when multiple copies of a transgene are inserted in tandem. BioEssays 24:828–835, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The chromocenter of Drosophila polytene chromosomes, which consists of two major chromatin types, has long been a troublesome region in molecular terms. The recent microcloning of part of this region, the isolation of a monoclonal antibody to a beta‐heterochromatin binding protein, and new in situ studies now shed a little more light on this chromosomal region.

Eukaryotes organize certain chromosomal intervals into domains capable of si lencing most genes. Examples of silencing domains include the HML/HMR loci and subtelomeric chromatin in yeast, the Barr body X chromosome in mammals, and the pericentric heterochromatin of Drosophila. Silencing chromatin is often correlated with more regularized nucleosomal array than that found in active chromatin, and transcriptional activators appear to be missing from their target sites in silent chromatin. In Drosophila, gene silencing by heterochromatin is often variegated, indicating (...) that a gene may escape silencing in some cells. In a recent study, Ahmad and Henikoff(1) show that a yeast activator can compete successfully with Drosophila heterochromatic silencing factors for target sites in DNA. This competition, together with developmental change in the stability of heterochromatin itself, decides the transcriptional state for a gene subject to heterochromatin repression. BioEssays 23:767–771, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Much of what we understand about heterochromatin formation in mammals has been extrapolated from forward genetic screens for modifiers of position‐effect variegation (PEV) in the fruit fly Drosophila melanogaster. The recent identification of the HUSH (Human Silencing Hub) complex suggests that more recent evolutionary developments contribute to the mechanisms underlying PEV in human cells. Although HUSH‐mediated repression also involves heterochromatin spreading through the reading and writing of the repressive H3K9me3 histone modification, clear orthologues of HUSH subunits are not (...) found in Drosophila but are conserved in vertebrates. Here we compare the insights into the mechanisms of PEV derived from genetic screens in the fly, the mouse and in human cells, review what is currently known about the HUSH complex and discuss the implications of HUSH‐mediated silencing for viral latency. Future studies will provide mechanistic insight into HUSH complex function and reveal the relationship between HUSH and other epigenetic silencing complexes. (shrink)

Fluorescence microscopy has provided a route to qualitatively analyze features of nuclear structures and chromatin domains with increasing resolution. However, it is becoming increasingly important to develop tools for quantitative analysis. Here, we present an automated method to quantitatively determine the enrichment of several endogenous factors, immunostained in pericentric heterochromatin domains in mouse cells. We show that this method permits an unbiased characterization of changes in the enrichment of several factors with statistical significance from a large number of nuclei. (...) Furthermore, the nuclei can be sorted according to the enrichment value of these factors. This method should prove useful to monitor events related to changes in the amount, rather than the presence or absence, of any factor. By adapting a few parameters, it could be extended to other nuclear structures and the benefit of using available software will permit its use in many biological labs. (shrink)

Although the promyelocytic leukemia (PML) protein is renowned for regulating a wide range of cellular processes and as an essential component of PML nuclear bodies (PML‐NBs), the mechanisms through which it exerts its broad physiological impact are far from fully elucidated. Here, we review recent studies supporting an emerging view that PML's pleiotropic effects derive, at least partially, from its role in regulating histone H3.3 chromatin assembly, a critical epigenetic mechanism. These studies suggest that PML maintains heterochromatin organization by (...) restraining H3.3 incorporation. Examination of PML's contribution to H3.3 chromatin assembly in the context of the cell cycle and PML‐NB assembly suggests that PML represses heterochromatic H3.3 deposition during S phase and that transcription and SUMOylation regulate PML's recruitment to heterochromatin. Elucidating PML’ s contributions to H3.3‐mediated epigenetic regulation will provide insight into PML's expansive influence on cellular physiology and open new avenues for studying oncogenesis linked to PML malfunction. (shrink)

Graphical AbstractThe loosening of chromatin structures gives rise to unrestricted access to DNA and thus transcription factors (TFs) can bind to their otherwise masked target sequences. Regions bound by the same set of TFs tend to be located in close proximity and this might increase the probability of activating illegitimate genomic rearrangements.

Variegated phenotypes often result from chromosomal rearrangements that place euchromatic genes next to heterochromatin. In such rearrangements, the condensed structure of heterochromatin can spread into euchromatic regions, which then assume the morphology of heterochromatin and become transcriptionally inactive. In position‐effect variegation (PEV) therefore, gene inactivation results from a change in chromatin structure. PEV has been intensively investigated in the fruitfly Drosophila, where the phenomenon allows a genetic dissection of chromatin components. Consequently, many genes have been identified which, (...) when mutated, act as dominant modifiers (suppressors or enhancers) of PEV. Data available already demonstrate that genetic, molecular and developmental analysis of these genes provides an avenue to the identification of regulatory and structural chromatin components, and hence to fundamental aspects of chromosome structure and function. (shrink)

Expression of transgenes in mice, when examined with assays that can distinguish individual cells, is often found to be heterocellular, or variegated. Line‐to‐line variations in expression of a transgene may be due largely to differences in the proportion of cells in which it is expressed. Variegated silencing by centromeric heterochromatin is well described, but other factors may also affect transgene silencing in mice. Tandem arrays of transgenes themselves form heterochromatin, and some cell lineages may tend to silence transgenes (...) because of extensive facultative heterochromatin in their nuclei. The cis‐acting transcriptional control elements within a transgene inhibit silencing, and strainspecific differences in chromatin proteins may strongly influence the extent of variegation. The accessibility of multiple differentiated cell lineages in mice suggests that they may provide a tool for dissecting the role of chromatin‐mediated silencing in cell differentiation and tissue‐specific gene expression. (shrink)

We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long‐range transcriptional regulation. Several observations suggest that TADs (...) can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied. (shrink)

Transcription in organisms as diverse as yeast and mammals is subject to chromosomal position effects that result in heritable and variegated patterns of gene expression. Two recent studies have employed a reversible protein‐DNA crosslinking method to identify the structural components of heterochromatin in budding yeast(1,2). The results show that a complex containing the proteins Rap1, Sir2p, Sir3p and Sir4p is physically associated with nucleosomes at telomere proximal regions, but that the repressive chromatin structure extended by Sir3p overexpression has a (...) different composition. (shrink)

The use of Drosophila chromosomal rearrangements and transposon constructs involving the white gene reveals the existence of repressive chromatin domains that can spread over considerable genomic distances. One such type of domain is found in heterochromatin and is responsible for classical position‐effect variegation. Another type of repressive domain is established, beginning at specific sequences, by complexes of Polycomb Group proteins. Such complexes, which normally regulate the expression of many genes, including the homeotic loci, are responsible for silencing, white gene (...) variegation, pairing‐dependent effects and insertional targeting. (shrink)

Here we present and develop the hypothesis that the derepression of endogenous retrotransposable elements (RTEs) – “genomic parasites” – is an important and hitherto under‐unexplored molecular aging process that can potentially occur in most tissues. We further envision that the activation and continued presence of retrotransposition contribute to age‐associated tissue degeneration and pathology. Chromatin is a complex and dynamic structure that needs to be maintained in a functional state throughout our lifetime. Studies of diverse species have revealed that chromatin undergoes (...) extensive rearrangements during aging. Cellular senescence, an important component of mammalian aging, has recently been associated with decreased heterochromatinization of normally silenced regions of the genome. These changes lead to the expression of RTEs, culminating in their transposition. RTEs are common in all kingdoms of life, and comprise close to 50% of mammalian genomes. They are tightly controlled, as their activity is highly destabilizing and mutagenic to their resident genomes. (shrink)

Specificities associated with chromosomal linearity are not restricted to telomeres. Here, recent results obtained on fission and budding yeast are summarized and an attempt is made to define subtelomeres using chromatin features extending beyond the heterochromatin emanating from telomeres. Subtelomeres, the chromosome domains adjacent to telomeres, differ from the rest of the genome by their gene content, rapid evolution, and chromatin features that together contribute to organism adaptation. However, current definitions of subtelomeres are generally based on synteny and are (...) largely gene‐centered. Taking into consideration both the peculiar gene content and dynamics as well as the chromatin properties of those domains, it is discussed how chromatin features can contribute to subtelomeric properties and functions, and play a pivotal role in the emergence of subtelomeres. (shrink)

The RNAi machinery is not only involved with post‐transcriptional degradation of messenger RNAs, but also used for targeting of chromatin changes associated with transcriptional silencing. Two recent papers determine the global patterns of gene expression and chromatin modifications produced by the RNAi machinery in fission yeast.(9, 10) The major sites include the outer centromere repeats, the mating‐type locus and subtelomeric regions. By comparison, studies of Arabidopsis heterochromatin also implicate transposons as a major target for silencing. Analyses of siRNA libraries (...) from Drosophila, nematodes and Arabidopsis indicate that major repeats at centromeres, telomeres and transposable elements are likely targets of RNAi. Also, intergenic regions are implicated as targets in Arabidopsis. BioEssays 27:1209–1212, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Somatic mutations arising in human skin cancers are heterogeneously distributed across the genome, meaning that certain genomic regions (e.g., heterochromatin or transcription factor binding sites) have much higher mutation densities than others. Regional variations in mutation rates are typically not a consequence of selection, as the vast majority of somatic mutations in skin cancers are passenger mutations that do not promote cell growth or transformation. Instead, variations in DNA repair activity, due to chromatin organization and transcription factor binding, have (...) been proposed to be a primary driver of mutational heterogeneity in melanoma. However, as discussed in this review here, recent studies indicate that chromatin organization and transcription factor binding also significantly modulate the rate at which UV lesions form in DNA. The authors propose that local variations in lesion susceptibility may be an important driver of mutational hotspots in melanoma and other skin cancers, particularly at binding sites for ETS transcription factors. (shrink)

Classically, position effect variegation has been studied in Drosophila and results when a euchromatic gene is placed adjacent to either centromeric heterochromatin or to a telomeric domain. In such a circumstance expression of the locus variegates, being active in some cells and silent in others. Over the last few years a comparable phenomenon in yeast has been discovered. This system promises to tell us much about this curious behaviour. Indeed, experiments reported recently(1) indicate that the variegation of a yeast (...) telomeric gene is cell‐cycle regulated. The results suggest the following model. During DNA replication there is a disassembly of chromatin that allows a competition between silencing factors and trans‐activators to take place. Thus, reassembly of the domain may result in either the repression or the expression of the affected gene and, hence, produce a variegating phenotype. (shrink)

The chromosomes which segregate in anaphase I of meiosis are usually physically bound together through chiasmata. This association is necessary for proper segregation, since univalents sort independently from one another in the first meiotic division and this frequently leads to genetically unbalanced offspring. There are, however, a number of species where genetic exchanges in the form of meiotic cross‐overs, the prerequisite of the formation of chiasmata, are routinely missing in one sex or between specific chromosomes. These species nevertheless manage to (...) segregate these non‐exchange chromosomes. There are four direct modes for associating achiasmatic chromosomes: (a) modified SC, (b) adhesion of chromatids comparable to somatic pairing, (c) ‘stickiness’ of heterochromatin or (d) specific ‘segregation bodies’, consisting of material structurally different from chromatin. There is also the possibility that the spindlepossibly joining forces with the kinetochores‐carries out the faithful segregation of univalents which are not directly physically attached to one another. Finally, amphitelic orientation of univalents in metaphase I and pairing of the chromatids in meiosis II appear to ensure correct segregation as well. (shrink)

This article focuses on the role of the interchromatin compartment (IC) in shaping nuclear landscapes. The IC is connected with nuclear pore complexes (NPCs) and harbors splicing speckles and nuclear bodies. It is postulated that the IC provides routes for imported transcription factors to target sites, for export routes of mRNA as ribonucleoproteins toward NPCs, as well as for the intranuclear passage of regulatory RNAs from sites of transcription to remote functional sites (IC hypothesis). IC channels are lined by less‐compacted (...) euchromatin, called the perichromatin region (PR). The PR and IC together form the active nuclear compartment (ANC). The ANC is co‐aligned with the inactive nuclear compartment (INC), comprising more compacted heterochromatin. It is postulated that the INC is accessible for individual transcription factors, but inaccessible for larger macromolecular aggregates (limited accessibility hypothesis). This functional nuclear organization depends on still unexplored movements of genes and regulatory sequences between the two compartments. (shrink)

X‐chromosome inactivation refers to the coordinate regulation of almost all genes on the mammalian × chromosome. Most models for × chromosome inactivation suppose a role for methylation of × chromosome DNA sequences and/or the heterochromatinization of large «domains» of the × chromosome containing many genes.1 Some recent work concerning the expression of X‐linked transgenes, and parallels between regulated expression of sex‐linked genes in invertebrates and mammals, suggest that × chromosome inactivation may be a gene‐by‐gene event mediated by the interaction between (...) regulatory sequences common to all X‐linked genes and soluble activators and repressors. (shrink)

From the viewpoint of an evolutionary biologist, carcinogenesis should be looked upon as a protective mechanism against destruction of DNA. Because genes expressed in embryonic cells are covered and protected by heterochromatinization, they are the most appropriate ‘alternate genes’ compared to genes that are expressed already in somatic cells. When DNA-damage occurs, the embryonic genes can be activated. Some somatic cells exhibit some features of embryonic cells.

The Segregation Distorter (SD) system of Drosophila melanogaster is one the best‐characterized meiotic drive complexes known. SD gains an unfair transmission advantage through heterozygous SD/SD+ males by incapacitating SD+‐bearing spermatids so that virtually all progeny inherit SD. Segregation distorter (Sd), the primary distorting locus in the SD complex, is a truncated duplication of the RanGAP gene, a major regulator of the small GTPase Ran, which has several functions including the maintenance of the nucleocytoplasmic RanGTP concentration gradient that mediates nuclear transport. (...) The truncated Sd‐RanGAP protein is enzymatically active but mislocalizes to the nucleus where it somehow causes distortion. Here I present data consistent with the idea that wild‐type RanGAP, and possibly other loci able to influence the RanGTP gradient, has been caught up in an ancient genetic conflict that predates the SD complex. The legacy of this conflict could include the unexpectedly rapid evolution of nuclear transport‐related proteins, the accumulation of chromosomal inversions, the recruitment of gene duplications, and the turnover of repetitive sequences in the centric heterochromatin. BioEssays 29:386–391, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Genomes of higher eukaryotes contain abundant non‐coding repeated sequences whose overall biological impact is unclear. They comprise two categories. The first consists of retrotransposon‐derived elements. These are three major families of retroelements (LINEs, SINEs and LTRs). SINEs are clustered in gene‐rich regions and are found in promoters of genes while LINEs are concentrated in gene‐poor regions and are depleted from promoters. The second class consists of non‐coding tandem repeats (satellite DNAs and TTAGGG arrays), which are associated with mammalian centromeres, (...) class='Hi'>heterochromatin and telomeres. Terminal TTAGGG arrays are involved in telomere capping and satellite DNAs are located in heterochromatin, which is implicated in transcription silencing by gene repositioning (relocalization). It is unknown whether interstitial TTAGGG sequences, which are present in many vertebrates, have a function. Here, evidence will be presented that retroelements and TTAGGG arrays are involved in regulation of gene expression. Retroelements can provide binding sites for transcription factors and protect promoter CpG islands from repressive chromatin modifications, and may be also involved in nuclear compartmentalization of transcriptionally active and inactive domains. Interstitial telomere‐like sequences can form dynamically maintained three‐dimensional nuclear networks of transcriptionally inactive domains, which may be involved in transcription silencing like classic heterochromatin. BioEssays 30:338–348, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Methyl CpG binding protein 2 (MeCP2) was initially isolated as an exclusive reader of DNA methylated at CpG. This recognition site, was subsequently extended to other DNA methylated residues and it has been the persisting dogma that binding to methylated DNA constitutes its physiologically relevant role. As we review here, two very recent papers fundamentally change our understanding of the interactions of this protein with chromatin, as well as its functional attributes. In the first one, the protein has been shown (...) to bind to tri‐methylated histone H3 (H3K27me3), providing a hint for what might turn out to be the first described chromodomain‐containing protein reader in the animal kingdom, and unequivocally demonstrates the ability of MeCP2 to bind to nonmethylated CpG regions of the genome. The second paper reports how the protein dynamically participates in the formation of constitutive heterochromatin condensates. Histone H3K27me3 is a critical component of this form of chromatin. (shrink)

Acetylation of histones is an essential element regulating chromatin structure and transcription. MYST (Moz, Ybf2/Sas3, Sas2, Tip60) proteins form the largest family of histone acetyltransferases and are present in all eukaryotes. Surprisingly, until recently this protein family was poorly studied. However, in the last few years there has been a substantial increase in interest in the MYST proteins and a number of key studies have shown that these chromatin modifiers are required for a diverse range of cellular processes, both in (...) health and disease. Translocations affecting MYST histone acetyltransferases can lead to leukemia and solid tumors. Some members of the MYST family are required for the development and self‐renewal of stem cell populations; other members are essential for the prevention of inappropriate heterochromatin spreading and for the maintenance of adequate levels of gene expression. In this review we discuss the function of MYST proteins in vivo. (shrink)

The formation of a highly condensed chromosome structure (heterochromatin) in a region of a eukaryotic chromosome can inactivate the genes within that region. Genetic studies using the fruitfly Drosophila melanogaster have identified several essential genes which influence the formation of heterochromatin. My purpose in this review is to summarize some recent work on the genetics of heterochromatin assembly in Drosophila and a recent model for how chromosomal proteins may interact to form a heterochromatic structure.

X chromosome inactivation (XCI) is an essential epigenetic process that ensures X‐linked gene dosage equilibrium between sexes in mammals. XCI is dynamically regulated during development in a manner that is intimately linked to differentiation. Numerous studies, which we review here, have explored the dynamics of X inactivation and reactivation in the context of development, differentiation and diseases, and the phenotypic and molecular link between the inactive status, and the cellular context. Here, we also assess whether XCI is a uniform mechanism (...) in mammals by analyzing epigenetic signatures of the inactive X (Xi) in different species and cellular contexts. It appears that the timing of XCI and the epigenetic signature of the inactive X greatly vary between species. Surprisingly, even within a given species, various Xi configurations are found across cellular states. We discuss possible mechanisms underlying these variations, and how they might influence the fate of the Xi. (shrink)

The most enigmatic feature of polytene chromosomes is their banding pattern, the genetic organization of which has been a very attractive puzzle for many years. Recent genome‐wide protein mapping efforts have produced a wealth of data for the chromosome proteins of Drosophila cells. Based on their specific protein composition, the chromosomes comprise two types of bands, as well as interbands. These differ in terms of time of replication and specific types of proteins. The interbands are characterized by their association with (...) “active” chromatin proteins, nucleosome remodeling, and origin recognition complexes, and so they have three functions: acting as binding sites for RNA pol II, initiation of replication and nucleosome remodeling of short fragments of DNA. The borders and organization of the same band and interband regions are largely identical, irrespective of the cell type studied. This demonstrates that the banding pattern is a universal principle of the organization of interphase polytene and non‐polytene chromosomes.Editor's suggested further reading in BioEssaysCaught in the act: Rapid, symbiont‐driven evolution AbstractFunction and evolution of sex determination mechanisms, genes and pathways in insects Abstract. (shrink)

Nucleosomes “talk” to each other about their modification state to form extended domains of modified histones independently of the underlying DNA sequence. At the same time, DNA elements promote modification of nucleosomes in their vicinity. How do these site-specific and histone-based activities act together to regulate spreading of histone modifications along the genome? How do they enable epigenetic memory to preserve cell identity? Many models for the dynamics of repressive histone modifications emphasize the role of strong positive feedback loops, which (...) reinforce histone modifications by recruiting histone modifiers to preexisting modifications. Recent experiments question that repressive histone modifications are self-sustained independently of their genomic context, thereby indicating that histone-based feedback is relatively weak. In the present review, current models for the dynamics of histone modifications are compared and it is suggested that limitation of histone-based feedback is key to intrinsic confinement of spreading and coexistence of short- and long-term memory at different genomic loci. See also the video abstract here: https://youtu.be/3bxr_xDEZfQ. Communication between nucleosomes and site-specific recruitment of histone modifiers act together to enable spreading and epigenetic memory of histone modifications. This review essay compares current models that describe these phenomena and outline a mechanism for how epigenetic short- and long-term memory can coexist in the same cell. (shrink)