Chromatin is a complex of DNA and protein responsible for condensing and packaging chromosomal DNA. Chromatin is found in both bacterial and eukaryotic cells.
Eukaryotic chromatin consists primarily of DNA associated with histone proteins and numerous other chromatin-binding factors that contribute to genome organization and regulation. Chromatin packages long DNA molecules into compact structures while controlling access to genetic information for processes such as transcription, DNA replication, and DNA repair. During cell division, chromatin facilitates proper segregation of chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.
Chromatin organization is often described at several structural levels. At the most basic level, DNA wrapped around histone octamers forms nucleosomes connected by stretches of linker DNA, producing a structure sometimes referred to as a “beads-on-a-string” fiber approximately 10–11 nm in diameter. Nucleosome arrays can interact with each other and with linker histones to form higher-order chromatin structures. 30-nm chromatin fiber has been observed in vitro, although its presence and prevalence in living cells remain debated.
At larger genomic scales, chromatin is organized into loops and domains that contribute to the three-dimensional architecture of the genome. Chromosomes are further partitioned into compartments associated with active (euchromatin) or inactive (heterochromatin) chromatin states, and individual chromosomes occupy distinct spatial regions within the nucleus known as chromosome territories.
Many organisms exhibit variations in chromatin organization. For example, spermatozoa and avian red blood cells have more tightly packed chromatin than most eukaryotic cells. In contrast, some protozoa such as trypanosomatid do not DNA condense their chromatin into visible chromosomes at all.
Bacteria organize their DNA differently, forming a chromatin or nucleoid structure organized by nucleoid-associated proteins including H-NS and StpA. Some archaeal species encode histone proteins, and package DNA into nucleosome-like assemblies of variable size, sometimes referred to as hypernucleosomes.
Chromatin organization also varies throughout the cell cycle. During interphase, chromatin is generally less condensed, allowing access to RNA and DNA polymerases that transcribe and replicate the DNA. The local structure of chromatin during interphase depends on the specific genes present in the DNA.
During mitosis and meiosis, chromatin becomes highly compacted to facilitate the segregation of chromosomes. Within interphase nuclei, genomic regions differ in their degree of compaction and transcriptional activity. Actively transcribed regions are often associated with less condensed chromatin known as euchromatin, whereas transcriptionally inactive or repressed regions are frequently enriched in more compact heterochromatin. Chemical modifications of chromatin components, often so-called epigenetic modification, including histone tails methylation and acetylation also alters local chromatin structure and therefore gene expression.
Basic chromatin structure
Nucleosomes
The primary protein components of chromatin are histones. Nucleosome, the fundamental basic unit of chromatin, consists of DNA wrapped around a histone octamer containing two copies each of the core histones Histone H2A, Histone H2B, Histone H3, and Histone H4. Approximately 147 base pairs of DNA wrap around this histone octamer to form the nucleosome core particle. Neighboring nucleosomes are connected by stretches of linker DNA, which vary in length among organisms and cell types but typically range from about 20 to 60 base pairs. Arrays of nucleosomes connected by linker DNA form an extended fiber often described as a “beads-on-a-string” structure approximately 10–11 nm in diameter under low-salt or experimentally reconstituted conditions.
In addition to core histones, a linker histone H1 binds near the entry and exit sites of DNA on the nucleosome and contributes to higher-order chromatin organization. The nucleosome core particle, together with histone H1, is known as a chromatosome.
The nucleosomes bind DNA non-specifically, as required by their function in general DNA packaging. There are, however, large DNA sequence preferences that govern nucleosome positioning. This is due primarily to the varying physical properties of different DNA sequences: For instance, adenine (A), and thymine (T) is more favorably compressed into the inner minor grooves. This means nucleosomes can bind preferentially at one position approximately every 10 base pairs (the helical repeat of DNA)- where the DNA is rotated to maximize the number of A and T bases that will lie in the inner minor groove (see nucleic acid structure).
Historical 30-nm fiber model
Under certain experimental conditions, nucleosome arrays can fold into more compact structures with diameters of approximately 30 nm. Early models proposed that chromatin fibers adopt regular helical arrangements, including a one-start solenoid model and a two-start zigzag model.
However, the existence of a uniform 30-nm chromatin fiber in living cells remains debated. Studies using cryo-electron microscopy and other high-resolution imaging methods have suggested that chromatin in many cell types forms irregular and dynamic nucleosome assemblies rather than regular 30-nm fibers.
Three-dimensional genome organization see Nuclear organization
Chromatin loops
The beads-on-a-string chromatin structure has a tendency to form loops. These loops allow interactions between different regions of DNA by bringing them closer to each other, which increases the efficiency of gene interactions. This process is dynamic, with loops forming and disappearing. The loops are regulated by two main elements: Cohesins, protein complexes that generate loops by extrusion of the DNA fiber through the ring-like structure of the complex itself. CTCF, a transcription factor that limits the frontier of the DNA loop. To stop the growth of a loop, two CTCF molecules must be positioned in opposite directions to block the movement of the cohesin ring (see video). There are many other elements involved. For example, Jpx regulates the binding sites of CTCF molecules along the DNA fiber.
TADs see Topologically associating domain
Chromatin compartments Chromatin compartments are large-scale structural domains of the genome that reflect the segregation of chromatin with similar transcriptional and epigenetic properties. Genome-wide chromosome conformation capture experiments have revealed that chromosomes are partitioned into at least two major compartment types, commonly referred to as A and B compartments. A compartments are generally enriched in transcriptionally active chromatin, open chromatin marks, and gene-rich regions, whereas B compartments are associated with transcriptionally inactive chromatin, heterochromatin, and interactions with nuclear structures such as the nuclear lamina. These compartments represent preferential long-range interactions between genomic regions with similar chromatin states and contribute to the spatial organization of chromosomes within the nucleus.
Chromosome territories see Chromosome territories
Chromatin dynamics and regulation
Histone modifications Chromatin structure is highly dynamic and changes throughout the cell cycle and in response to cellular signals. Histone proteins play a central role in organizing chromatin and can undergo a wide range of post-translational modifications, including acetylation, methylation, phosphorylation, and ubiquitination (see histone modification). These modifications occur primarily on the flexible N-terminal tails of histones that extend outward from the nucleosome core.
The positively charged histone cores only partially counteract the negative charge of the DNA phosphate backbone resulting in a negative net charge of the overall structure. An imbalance of charge within the polymer causes electrostatic repulsion between neighboring chromatin regions that promote interactions with positively charged proteins, molecules, and cations. As these modifications occur, the electrostatic environment surrounding the chromatin will flux and the level of chromatin compaction will alter. The consequences in terms of chromatin accessibility and compaction depend both on the modified amino acid and the type of modification.
Different histone modifications are associated with distinct chromatin states. For example, histone acetylation is generally correlated with increased chromatin accessibility and active transcription, whereas certain histone methylation marks are associated with either transcriptional activation (trimethylation of histone H3 lysine 4) or repression (trimethylation of histone H3, lysine 9 or lysine 27) depending on the modified residue.
Multiple histone modifications can occur simultaneously on the same nucleosome, creating combinations of regulatory signals sometimes referred to as the histone code. For example, developmental genes in mammalian embryonic stem cells often carry both activating (H3K4me3) and repressive (H3K27me3) marks in a configuration known as bivalent structure, which is involved into cell fate transtition during early mammalian development.
Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure.
Enzymes that add, remove, or recognize histone modifications are often described as chromatin writers, erasers, and readers, respectively. For additional information, see Chromatin variant, Histone modifications in chromatin regulation and RNA polymerase control by chromatin structure.
Chromatin remodeling see Chromatin remodeling
Transcriptional bursting Main page: Transcriptional burstingChromatin and its interaction with enzymes has been researched, and a conclusion being made is that it is relevant and an important factor in gene expression. Vincent G. Allfrey, a professor at Rockefeller University, stated that RNA synthesis is related to histone acetylation. The lysine amino acid attached to the end of the histones is positively charged. The acetylation of these tails would make the chromatin ends neutral, allowing for DNA access.
When the chromatin decondenses, the DNA is open to entry of molecular machinery. Fluctuations between open and closed chromatin may contribute to the discontinuity of transcription, or transcriptional bursting. Other factors are probably involved, such as the association and dissociation of transcription factor complexes with chromatin. Specifically, RNA polymerase and transcriptional proteins have been shown to congregate into droplets via phase separation, and recent studies have suggested that 10 nm chromatin demonstrates liquid-like behavior increasing the targetability of genomic DNA.Maeshima, K., Ide, S., Hibino, K., & Sasai, M. (2016). Liquid-like behavior of chromatin. Current opinion in genetics & development, 37, 36–45. https://doi.org/10.1016/j.gde.2015.11.006 The interactions between linker histones and disordered tail regions act as an electrostatic glue organizing large-scale chromatin into a dynamic, liquid-like domain. Decreased chromatin compaction comes with increased chromatin mobility and easier transcriptional access to DNA. The phenomenon, as opposed to simple probabilistic models of transcription, can account for the high variability in gene expression occurring between cells in isogenic populations.
Structure of DNA