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Intelligent Design, the best explanation of Origins » Intelligent Design » Chromatin Remodeling in Eukaryotes

Chromatin Remodeling in Eukaryotes

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1 Chromatin Remodeling in Eukaryotes on Mon Jun 15, 2015 7:48 pm

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Chromatin Remodeling in Eukaryotes 1

http://www.nature.com/scitable/topicpage/Chromatin-Remodeling-in-Eukaryotes-1082

chromatin not only serves as a way to condense DNA within the cellular nucleus, but also as a way to control how that DNA is used. In particular, within eukaryotes, specific genes are not expressed unless they can be accessed by RNA polymerase and proteins known as transcription factors. In its default state, the tight coiling that characterizes chromatin structure limits the access of these substances to eukaryotic DNA. Therefore, a cell's chromatin must "open" in order for gene expression to take place. This process of "opening" is called chromatin remodeling, and it is of vital importance to the proper functioning of all eukaryotic cells. In recent years, researchers have discovered a great deal about chromatin remodeling, including the roles that different protein complexes, histone variants, and biochemical modifications play in this process. However, a great deal remains to be learned before chromatin remodeling is fully understood.

Chromatin Remodeling at a Glance

Various molecules called chromatin remodelers provide the mechanism for modifying chromatin and allowing transcription signals to reach their destinations on the DNA strand. Understanding the nature and processes of these cellular construction workers remains an active area of discovery in genetic research.

Currently, investigators know that chromatin remodelers are large, multiprotein complexes that use the energy of ATP hydrolysis to mobilize and restructure nucleosomes. Recall that nucleosomes wrap 146 base pairs of DNA in approximately 1.7 turns around a histone-octamer disk, and the DNA inside each nucleosome is generally inaccessible to DNA-binding factors. Remodelers are thus necessary to provide access to the underlying DNA to enable transcription, chromatin assembly, DNA repair, and other processes. Just how remodelers convert the energy of ATP hydrolysis into mechanical force to mobilize the nucleosome, and how different remodeler complexes select which nucleosomes to move and restructure, remains unknown, however.

Remodelers are partitioned into five families, each with specialized biological roles. Nonetheless, all remodelers contain a subunit with a conserved ATPase domain. In addition to the conserved ATPase, each remodeler complex also possesses unique proteins that specialize it for its unique biological role. However, because all remodelers move nucleosomes and all such movement is ATP dependent, mobilization is most likely a property of the conserved ATPase subunit.

The ATPase domains of remodelers are similar in sequence and structure to known DNA-translocating proteins in viruses and bacteria. Recent evidence from the SWI/SNF and ISWI remodeler families has also revealed that remodeler ATPases are directional DNA translocases that are capable of the directional pumping of DNA. But how is this property applied to nucleosomes? It seems that the ATPase binds approximately 40 base pairs inside the nucleosome, from which location it pumps DNA around the histone-octamer surface. This enables the movement of the nucleosome along the DNA, thus permitting the exposure of the DNA to regulatory factors.

The additional domains and proteins that are attached to the ATPase are important for nucleosome selection, and they also help regulate ATPase activity. These attendant proteins bind to histones and nucleosomal DNA, and their binding to these molecules is affected by the histone modification state. The modification state helps determine whether the nucleosome is an appropriate substrate for a remodeler complex (Saha et al., 2006), as discussed later in this article.

Indeed, canonical histones can themselves be replaced by histone variants or modified by specific enzymes, thereby making the surrounding DNA more or less accessible to the transcriptional machinery.

So far, a number of histone variants have been found and localized to specific areas of chromatin. For instance, H2A.Z is a variant of H2A and is often enriched near relatively inactive gene promoters. Interestingly, H2A.Z does not take its place during replication when the chromatin structure is established. Instead, the chromatin remodeling complex SWR1 catalyzes an ATP-dependent exchange of H2A in the nucleosome for H2A.Z (Wu et al., 2005).

Histone Modification and the Histone Code

Histone sequences are highly conserved. The diagram below shows a typical chromatin fiber, with the blue cylinders representing histones. Extending from each of the histones is a "tail," called the N-terminal tail because proteins have two ends--an N terminus and C terminus. Here, the C terminus forms a globular domain that is packaged into the nucleosome. The other end of the histone is more flexible and capable of interacting more directly with DNA and the different proteins within the nucleus.


Figure below: (A) General chromatin organization. Like other histone "tails," the N terminus of H3 (red) represents a highly conserved domain that is likely to be exposed or extend outwards from the chromatin fiber. A number of distinct post-translational modifications are known to occur at the N terminus f H3 including acetylation (green flag), phosphorylation (grey circle), and methylation (yellow hexagon). Other modifications are known and may also occur in the globular domain. (B) The N terminus of human H3 is shown in single-letter amino-acid code. For comparison, the N termini of human CENP-A, a centromere-specific H3 variant, and human H4, the nucleosomal partner to H3, are shown. Note the regular spacing of acetylatable lysines (red), and potential phosphorylation (blue) and methylation (purple) sites. The asterisk indicates the lysine residue in H3 that is known to be targeted for acetylation as well as for methylation; lysine 9 in CENP-A (bold) may also be chemically modified (see text). The above depictions of chromatin structure and H3 are schematic; no attempt has been made to accurately portray these structures.





1)  http://www.nature.com/scitable/topicpage/Chromatin-Remodeling-in-Eukaryotes-1082

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2 Chromatin remodelers on Sat Jun 20, 2015 10:54 am

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chromatin remodelers

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, i.e., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes.[1] Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, e.g., DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency.

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3 Controlling the double helix on Thu Oct 22, 2015 10:58 pm

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Controlling the double helix

Chromatin is the complex of DNA and proteins in which the genetic material is packaged inside the cells of organisms with nuclei. Chromatin structure is dynamic and exerts profound control over gene expression and other fundamental cellular processes. Changes in its structure can be inherited by the next generation, independent of the DNA sequence itself.

Genes were first shown to be made of DNA only nine years before the structure of DNA was discovered. Although revolutionary, the idea that genetic information was protein-free ultimately proved too simple. DNA in organisms with nuclei is in fact coated with at least an equal mass of protein, forming a complex called chromatin, which controls gene activity and the inheritance of traits. ‘Higher’ organisms, such as yeast and humans, are eukaryotes; that is, they package their DNA inside cells in a separate compartment called the nucleus. In dividing cells, the chromatin complex of DNA and protein can be seen as individual compact chromosomes; in non-dividing cells, chromatin appears to be distributed throughout the nucleus and organized into ‘condensed’ regions (heterochromatin) and more open ‘euchromatin’ . In contrast, prokaryotes, such as bacteria, lack nuclei.

Packaging DNA into chromatin

The fundamental subunit of chromatin is the nucleosome, which consists of approximately 165 base pairs (bp) of DNA wrapped in two superhelical turns around an octamer of core histones (two each of histones H2A, H2B, H3 and H4). This results in a five- to tenfold compaction of DNA6. The DNA wound around the surface of the histone octamer (Fig. 1) is partially accessible to regulatory proteins, but could become more available if the nucleosome could be moved out of the way, or if the DNA partly unwound from the octamer. The
histone ‘tails’ (the amino-terminal ends of the histone protein chains) are also accessible, and enzymes can chemically modify these tails to promote nucleosome movement and unwinding, with profound local effects on the chromatin complex. Each nucleosome is connected to its neighbours by a short segment of linker DNA (~10–80 bp in length) and this polynucleosome string is folded into a compact fibre with a diameter of ~30 nm, producing a net compaction of roughly 50-fold. The 30-nm fibre is stabilized by the binding of a fifth histone, H1, to each nucleosome and to its adjacent linker. There is still considerable debate about the finer points of nucleosome packing within the chromatin fibre, and
even less is known about the way in which these fibres are further packed within the nucleus to form the highest-order structures.

Chromatin regulates gene expression

Regulatory signals entering the nucleus encounter chromatin, not DNA, and the rate-limiting biochemical response that leads to activation of gene expression in most cases involves alterations in chromatin structure. How are such alterations achieved? The most compact form of chromatin is inaccessible and therefore provides a poor template for biochemical reactions such as transcription, in which the DNA duplex must serve as a template for RNA polymerase. Nucleosomes associated with active genes were shown to be more accessible to enzymes that attack DNA than those associated with inactive genes, which is consistent with the idea that activation of gene expression should involve selective disruption of the folded structure. Clues as to how chromatin is unpacked came from the discovery that components of chromatin are subject to a wide range of modifications that are correlated with gene activity. Such modifications probably occur at every level of organization, but most attention has focused on the nucleosome itself. There are three general ways in which chromatin structure can be altered. First, nucleosome remodelling can be induced by complexes designed specifically for the task; this typically requires that energy be expended by hydrolysis of ATP. Second, covalent modification of histones can occur within the nucleosome. Third, histone variants may replace one or more of the core histones. Some modifications affect nucleosome structure or lability directly, whereas others introduce chemical groups that are recognized by additional regulatory or structural proteins. Still others may be involved in disruption of higher-order structure. In some cases, the packaging of particular genes in chromatin is required for their expression. Thus, chromatin can be involved in both activation and repression of gene expression.

Chromatin remodelling

Transcription factors regulate expression by binding to specific DNA control sequences in the neighbourhood of a gene. Although some DNA sequences are accessible either as an outward-facing segment on the nucleosome surface, or in linkers between nucleosomes, most are buried inside the nucleosome. Regulatory factors must therefore seek out their specific DNA-binding sites and gain access to them. They are aided by chromatin-remodelling complexes that continually shuffle the positions of individual nucleosomes so that sites are randomly exposed for a fraction of time. A number of chromatin-remodelling complexes mobilize nucleosomes, causing the histone octamers to move short distances along the DNA. Each complex carries a protein with ATPase activity, which provides the necessary energy. Many of these complexes are members of the so-called SWI/SNF family, which includes SWI/SNF in budding yeast and human, RSC in yeast, and Brahma in Drosophila. They have similar helicase-motif subunits, but varying co-factors within the complex. Another SWI/SNF subfamily is based on the helicase-domain protein ISWI, which combines with other proteins to form the complexes NURF, CHRAC and ACF in Drosophila, and RSF in humans. A third subfamily is based on the helicase motif protein Mi-2. 2 Remodelling complexes differ in the mechanisms by which they disrupt nucleosome structure, and they are associated with cofactors that allow them to interact selectively with other regulatory proteins that bind to specific DNA sequences. For example, only certain classes of transcription factors interact with the mammalian SWI/SNF remodelling complex. Thus remodelling complexes can be selective in the genes they modify, and transcription factors recruit these complexes as tools to gain access to chromatin.

Histone modification

Nucleosomes are not passive participants in this recognition process. They can accommodate chemical modifications — either on histone ‘tails’ that extend from the nucleosome surface, or within the body of the octamer — that serve as signals for the binding of specific proteins. A large number of modifications are already known, such as acetylation of amino acids in the histone tails, and new ones are being identified at a bewildering rate (Box 1).



Many modifications are associated with distinct patterns of gene expression, DNA repair or replication, and it is likely that most or all modifications will ultimately be found to have distinct phenotypes. In addition to histone modifications, nucleosomes can have core histones substituted by a variant, with functional consequences. Histone H2AZ, which is associated with reduced nucleosome stability, replaces H2A non-randomly at specific sites in the genome. Histone H2AX, which is distributed throughout the genome, is a target of phosphorylation accompanying repair of DNA breakage, and also seems to be involved in the V(D)J recombination events that lead to the assembly of immunoglobulin and T-cell-receptor genes. A histone H3 variant, H3.3, can be incorporated into chromatin in non-dividing cells, and seems to be associated with transcriptionally active genes. Each of these histone substitutions is likely to be targeted by, and associated with, the binding of other proteins involved in gene activation; thus these proteins can be considered central to the formation of localized chromatin structures that are specific for gene activation or accessibility.

Interdependence of histone modifications

An interplay exists between histone modification and chromatin remodelling. For example, expression of a gene may require disruption of nucleosomes positioned at the promoter by a chromatin- remodelling complex before an enzyme required for histone acetylation can be recruited. In contrast, expression of a different gene may require that histone-acetylating enzymes and even RNA polymerase bind to the promoter prior to recruitment of the chromatin-remodelling complex. There is no common series of steps that underlies all or even most processes of gene activation. For any given gene, however, the order of recruitment of chromatinmodifying factors may be crucial for the appropriate timing of expression. Aside from activating gene expression, histone modifications and chromatin remodelling can also silence genes. Specific histone modifications and chromatin-remodelling complexes, such as the NuRD complex 3, have been implicated in silencing at some loci. Even SWI/SNF complexes, which are strongly correlated with gene activation, also seem to silence a number of genes.

1) http://www.nature.com/nature/journal/v421/n6921/abs/nature01411.html
2) http://microbiology.ucdavis.edu/kowalczykowski/pdf_files/thoma%20et%20al,%202005,%20nat%20struct%20mol%20biol,%2012%20350-356.pdf
3) http://www.nature.com/onc/journal/v26/n37/full/1210611a.html



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