Nucleosomes and Histone Proteins | amsbio
The fundamental unit of chromatin, termed the nucleosome, is composed of DNA . link between the assembly of chromatin and the processes of replication and. Nucleosomes fold up to form a nanometer chromatin fiber, which forms loops averaging nanometers . Nature Reviews Molecular Cell Biology 4, – () (link to article) Chromosome Abnormalities and Cancer Cytogenetics. Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation. Histone acetylation and deacetylation are essential parts of gene regulation. Acetylated histones, the octomeric protein cores of nucleosomes.
The acetyl group is removed by one of the HDAC enzymes during deacetylation, allowing histones to interact with DNA more tightly to form compacted nucleosome assembly. This increase in the rigid structure prevents the incorporation of transcriptional machinery, effectively silencing gene transcription.
Chromatin remodeling - Wikipedia
Another implication of histone acetylation is to provide a platform for protein binding. As a posttranslational modificationthe acetylation of histones can attract proteins to elongated chromatin that has been marked by acetyl groups.
It has been hypothesized that the histone tails offer recognition sites that attract proteins responsible for transcriptional activation. A model proposed that the acetylation of H3 histones activates gene transcription by attracting other transcription related complexes.
Therefore, the acetyl mark provides a site for protein recognition where transcription factors interact with the acetylated histone tails via their bromodomain. This specific addition of single or multiple modifications on histone cores can be interpreted by transcription factors and complexes which leads to functional implications. This process is facilitated by enzymes such as HATs and HDACs that add or remove modifications on histones, and transcription factors that process and "read" the modification codes.
The outcome can be activation of transcription or repression of a gene. For example, the combination of acetylation and phosphorylation have synergistic effects on the chromosomes overall structural condensation level and, hence, induces transcription activation of immediate early gene. In this way, acetylation patterns are transmitted and interconnected with protein binding ability and functions in subsequent cell generation.
Bromodomain[ edit ] The bromodomain is a motif that is responsible for acetylated lysine recognition on histones by nucleosome remodelling proteins. This suggests that specific histone site acetylation has a regulatory role in gene transcriptional activation.
Nucleosomes and Histone Proteins
HDACs expression and activity in tumor cells is very different from normal cells. The overexpression and increased activity of HDACs has been shown to be characteristic of tumorigenesis and metastasissuggesting an important regulatory role of histone deacetylation on oncogene expression. Vorinostat targets histone acetylation mechanisms and can effectively inhibit abnormal chromatin remodeling in cancerous cells.
Glucose and glutamine are the major carbon sources of most mammalian cells, and glucose metabolism is closely related to histone acetylation and deacetylation. Glucose availability affects the intracellular pool of acetyl-CoA, a central metabolic intermediate that is also the acetyl donor in histone acetylation. Glucose is converted to acetyl-CoA by the pyruvate dehydrogenase complex PDCwhich produces acetyl-CoA from glucose-derived pyruvate; and by adenosine triphosphate-citrate lyase ACLYwhich generates acetyl-CoA from glucose-derived citrate.
PDC and ACLY activity depend on glucose availability, which thereby influences histone acetylation and consequently modulates gene expression and cell cycle progression. SIRT7, which deacetylates H3K18 and thereby represses transcription of target genes, is activated in cancer to stabilize cells in the transformed state.
Histone acetylation and deacetylation - Wikipedia
Nutrients appear to modulate SIRT activity. For example, long-chain fatty acids activate the deacetylase function of SIRT6, and this may affect histone acetylation. In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.
In rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. Repeated cocaine administration in mice induces hyperacetylation of histone 3 H3 or histone 4 H4 at 1, genes in one brain "reward" region [the nucleus accumbens NAc ] and deacetylation at genes. Histological examination of tumors harboring the H3K27M mutation revealed a dramatic reduction in the levels of H3K27me3 Venneti et al.
Further molecular studies revealed that H3K27M as well as other histone lysine-to-methionine mutants act as dominant inhibitors of histone lysine methylation pathways in tissue culture Chan et al.
The precise mechanism of H3K27M action is still unclear. However, using an unbiased proteomic approach, we failed to detect increased enrichment of PRC2 subunits relative to wild-type H3. In contrast, we found increased association of the bromodomain protein BRD4, which is consistent with increased histone acetylation levels observed in H3K27M mutant cells Herz et al. It is also intriguing that mutations in genes encoding for the PRC2 components do not appear to be prevalent in these pediatric gliomas.
Recent studies of chondroblastoma and giant cell tumors of bone revealed additional histone H3. Histone gene mutations in cancer are not restricted to histone H3. Recent work in follicular lymphoma identified mutations in a number of histone H1 genes Lohr et al. Whereas histone H2A, H2B, H3, and H4 constitute the nucleosome core, histone H1 acts as a linker histone and is involved in chromatin compaction. Like H3 gene mutations, H1 gene mutations are primarily single amino acid substitutions; however, instead of occurring at a few specific positions, the H1 gene mutations are scattered throughout the H1 globular domain Lohr et al.
Molecular analysis of one of these mutants, H1SF, revealed that it has a reduced capacity to associate with chromatin Morin et al. This suggests that histone H1 may lead to defective chromatin compaction and cause transcriptional misregulation or result in genomic instability. It will be important to examine the molecular function of histone H1 gene mutations in B-cell lymphoma in more detail. Analysis of mutations that co-occur or are mutually exclusive to histone H3 gene mutations have been insightful.
Mutations of the IDH1 gene are particularly prevalent in glioma but are also detected in leukemias Parsons et al. IDH1 alterations occur in the substrate-binding site at position Arg, and most mutations convert this residue to histidine IDH1 RHalthough other substitutions have also been detected Parsons et al. During this step the newly incorporated histones are de-acetylated. Next the incorporation of linker histones is accompanied by folding of the nucleofilament into the 30nm fibre, the structure of which remains to be elucidated.
Two principal models exist: Finally, further successive folding events lead to a high level of organization and specific domains in the nucleus.
At each of the steps described above, variation in the composition and activity of chromatin can be obtained by modifying its basic constituents and the activity of stimulatory factors implicated in the processes of its assembly and disassembly. General steps in chromatin assembly. Maturation requires ATP to establish a regular spacing, and histones are de-acetylated 3.
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The incorporation of linker histones is accompanied by folding of the nucleofilament. Here the model presents a solenoid structure in which there are six nucleosomes per gyre 4. Further folding events lead ultimately to a defined domain organization within the nucleus 5. V- Variation in basic constituents In the first steps of chromatin assembly, the elementary particle can assume variations: All of these variations are capable of introducing differences in the structure and activity of chromatin.
The vast array of post-translational modifications of the histone tails summarized in Fig 2 such as acetylation, phosphorylation, methylation, ubiquitination, polyADP-ribosylationand their association with specific biological processes has led to a proposed hypothesis of a language, refered to as the "histone code", that marks genomic regions It must be emphasized that this code is a working hypothesis.
The code is "read"by other proteins or protein complexes that are capable of understanding and interpreting the profiles of specific modifications. The incorporation of histone variants may be important at specific domains of the genome: Growing evidence exists that H2A. Z has a role in modifying chromatin structure to regulate transcription.
During the maturation step, incorporation of linker histones, non-histone chromatin associated proteins, called HMG High Mobility Groupand other specific DNA-binding factors help to space and fold the nucleofilament. Therefore the early steps in assembly can have a great impact on the final characteristics of chromatin in specific nuclear domains. Histone interacting factors Acidic factors can form complexes with histones and enhance the process of histone deposition.
They act as histone chaperones by facilitating the formation of nucleosome cores without being part of the final reaction product. These histone-interacting factors, also called chromatin-assembly factors, can bind preferentially to a subset of histone proteins. CAF-1 is also capable of promoting the assembly of chromatin specifically coupled to the repair of DNA.