Nucleosome Topics

• dna strands
• dna sequences
• dna backbone
• minor groove
• minor grooves
• hydrogen bonding
• side chains
• ubiquitous distribution
• nucleosomes
• histones
• hydroxyl groups
• amino acids
• surface region
• acetylation
• amides
• physiological conditions
• dimer
• crystal structure
• phosphates
• h4

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Nucleosome, Nucleosome

These are due to the formation of two types of DNA binding sites within the octamer; the 11 site which uses the 1 helix from two adjacent histones and the L1L2 site formed by the L1 and L2 loops. Salt links and hydrogen bonding between both side chain basic and hydroxyl groups and main chain amides with the DNA backbone phosphates form the bulk of interactions with the DNA. This is important given that the ubiquitous distribution of nucleosomes along genomes requires it to be a non-sequence-specific DNA-binding factor. Although nucleosomes tend to prefer some DNA sequences over others Segal E. et al., "A genomic code for nucleosome positioning", Nature 442, 772-778 (17 August 2006) , they are capable of binding practically to any sequence, which is thought to be due to the flexibility in the formation of these water-mediated interactions. In addition, non-polar interactions are made between protein side chains and the deoxyribose groups, and an arginine side chain intercalates into the DNA minor groove at all 14 sites it faces the octamer surface.The distribution and strength of DNA binding sites about the octamer surface distorts the DNA within the nucleosome core. The DNA is non-uniformly bent and also contains twist defects. The twist of free B-form DNA in solution is 10.5 bp per turn, however, the overall twist of nucleosomal DNA is only 10.2 bp per turn, varying from a value of 9.4 to 10.9 bp per turn.

The N-terminal tails of histones H3 and H2B pass through a channel formed by the minor grooves of the two DNA strands, protruding from the DNA every 20 bp. The N-terminal tail of histone H4 on the other hand has a region of highly basic amino acids (16-25) which, in the crystal structure, forms an interaction with the highly acidic surface region of a H2A-H2B dimer of another nucleosome, being potentially relevant for the higher-order structure of nucleosomes. This interaction is thought to occur also under physiological conditions and suggests that acetylation of the H4 tail distorts the higher order structure of chromatin.

A chain of nucleosomes can be arranged in a 30 nm fiber , a compacted structure with a packing ratio of ~50 and whose formation is dependent on the presence of the H1 histone.

Later work showed that this repositioning did not require disruption of the histone octamer but was consistent with nucleosomes being able to slide along the DNA in cis . In 2008, It was further revealed that CTCF binding sites act as nucleosome positioning anchors so that, when used to align various genomic signals, multiple flanking nucleosomes can be readily identified . Although nucleosomes are intrinsically mobile, eukaryotes have evolved a large family of ATP-dependent chromatin remodelling enzymes to alter chromatin structure, many of which do so via nucleosome sliding.

Measurements of these rates using time resolved FRET revealed that DNA within the nucleosome remains fully wrapped for only 250ms before it is unwrapped for 10-50ms and then rapidly rewrapped . This implies that DNA does not need to be actively dissociated from the nucleosome but that there is a significant fraction of time during which it is fully accessible. Indeed, this can be extended to the observation that introducing a DNA binding sequence within the nucleosome increases the accessibility of adjacent regions of DNA when bound . This propensity for DNA within the nucleosome to breathe is predicted to have important functional consequences for all DNA binding proteins that operate in a chromatin environment.

The fact that most of the early post-translational modifications found were concentrated within the tail extensions that protrude from the nucleosome core lead to two main theories regarding the mechanism of histone modification. The first of the theories suggested that they may affect electrostatic interactions between the histone tails and DNA to loosen chromatin structure. Later it was proposed that combinations of these modifications may create binding epitopes with which to recruit other proteins . Recently, given that more modifications have been found in the structured regions of histones it has been put forward that these modifications may affect histone-DNA and histone-histone interactions within the nucleosome core.Some modifications have been shown to be correlated with gene silencing, others seem to be correlated with gene activation. Common modifications include acetylation, methylation or ubiquitination of lysine; methylation of arginine and phosphorylation of serine. The information stored in this way is considered epigenetic since it is not encoded in the DNA but is still inherited to daughter cells. The maintenance of a repressed or activated status of a gene is often necessary for cellular differentiation.

Interestingly, this diversification of histone function is restricted to H2A and H3, with H2B and H4 being mostly invariant. H2A can be replaced by H2AZ (which leads to reduced nucleosome stability) or H2AX (which is associated with DNA repair and T cell differentiation) whereas the inactive X chromosomes in mammals are enriched in macroH2A. H3 can be replaced by H3.3 (which correlates with activate genes) and in centromeres H3 is replaced by CENPA.

Remodelling enzymes have been shown to slide nucleosomes along DNA ,disrupt histone-DNA contacts to the extent of destabilising the H2A/H2B dimer and to generate negative superhelical torsion in DNA and chromatin . Recently, the Swr1 remodelling enzyme has been shown to introduce the variant histone H2A.Z into nucleosomes . At present, it is not clear if all of these represent distinct reactions or merely alternative outcomes of a common mechanism. What is shared between all, and indeed the hallmark of ATP-dependent chromatin remodelling, is that they all result in altered DNA accessibility.Studies looking at gene activation in vivo and, more astonishingly, remodelling in vitro has revealed that chromatin remodelling events and transcription-factor binding are cyclical and periodic in nature. While the consequences of this for the reaction mechanism of chromatin remodelling are not known, the dynamic nature of the system may allow it to respond faster to external stimuli.

Most recently, a new study examined dynamic changes in nucleosome repositioning during a global transcriptional reprogramming event to elucidate the effects on nucleosome displacement during genome-wide transcriptional changes in yeast ( Saccharomyces cerevisiae ) . The results suggested that nucleosomes that were localized to promoter regions are displaced in response to stress (like heat shock). In addition, the removal of nucleosomes usually corresponded to transcriptional activation and the replacement of nucleosomes usually corresponded to transcriptional repression, presumably because transcription factor binding sites became more or less accessible, respectively. In general, only one or two nucleosomes were repositioned at the promoter to effect these transcriptional changes. However, even in chromosomal regions that were not associated with transcriptional changes, nucleosome repositioning was observed, suggesting that the covering and uncovering of transcriptional DNA does not necessarily produce a transcriptional event.

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