DNA (1.8 turns, about 150 base pairs)
Fig. 1.2 Chromatin organization. (A) Nucleosomes are comprised of octamers of histone proteins (two each of histone subunits H2A, H2B, H3, and H4) encircled by 1.8 loops of 147 base pairs of DNA; histone H1 sits on the 20 to 80 nucleotide linker DNA between nucleosomes and helps stabilize the overall chromatin architecture. The histone subunits are positively charged, thus allowing the compaction of the negatively charged DNA. (B) The relative state of DNA unwinding (and thus access for transcription factors) is regulated by histone modification, for example, by acetylation, methylation, and/or phosphorylation (so-called “marks”); marks are dynamically written and erased. Certain marks such as histone acetylation “open up” the chromatin structure, whereas others, such as methylation of particular histone residues, tend to condense the DNA and lead to gene silencing. DNA itself can also be also be methylated, a modification that is associated with transcriptional inactivation.
base pair DNA segments wrapped around a central core of proteins called histones. Nucleosomes resemble beads joined by short DNA linkers; the entire structure is generically called chromatin. Importantly, the winding and compaction of chromatin in any given cell varies in different genomic regions. Thus, nuclear chromatin exists in two basic forms (visualizable by standard histology): (1) histochemically dense and transcriptionally inactive heterochromatin and (2) histochemically dispersed and transcriptionally active euchromatin. Because only euchromatin permits gene expression and thereby dictates cellular identity and activity, there are a host of mechanisms that tightly regulate the state of chromatin (described below).
DNA methylation. High levels of DNA methylation in gene regulatory elements typically result in chromatin condensation and transcriptional silencing. Like histone modifications (see later), DNA methylation is tightly regulated by methyltransferases, demethylating enzymes, and methylated-DNA-binding proteins.
Histone modifying factors. Nucleosomes are highly dynamic structures regulated by an array of nuclear proteins and post-translational modifications:
Chromatin remodeling complexes can reposition nucleosomes on DNA, exposing (or obscuring) gene regulatory elements such as promoters.
writer” complexes carry out more than 70 different covalent histone modifications generically denoted as marks. These include methylation, acetylation, and phosphorylation of specific histone amino acid residues: Histone methylation of lysines and arginines is accomplished by specific writer enzymes; methylation of histone lysine residues can lead to transcriptional activation or repression, depending on which histone residue is “marked.” Histone acetylation of lysine residues (occurring through histone acetyl transferases) tends to open up chromatin and increase transcription; histone deacetylases (HDAC) reverse this process, leading to chromatin condensation. Histone phosphorylation of serine residues can variably open or condense chromatin, to increase or decrease transcription, respectively.