Inactive chromatin

Enzyme activity ascribed to corepressors, which is the removal of acetyl groups from lysine residues of histone tails. Thereby the assembly of nucleosomes is maintained, which leads to a dense, transcriptional inactive chromatin structure. 

Transcriptionally inactive chromatin is densely packed during interphase as observed by electron microscopic smdies and is referred to as heterochro-matin transcriptionally active chromatin stains less densely and is referred to as euchromatin. Generally, euchromatin is repficated earfier than heterochromatin in the mammafian cell cycle (see below). 

Some of this differential expression is achieved by having different regions of chromatin available for transcription in cells from various tissues. For example, the DNA containing the P-globin gene cluster is in active chromatin in the reticulocyte but in inactive chromatin in muscle cells. All the factors involved in the determination of active chromatin have not been elucidated. The presence of nucleosomes and of complexes of histones and DNA (see Chapter 36) certainly provides a barrier against the ready association of transcription fac-... 

Histone acetylases (fevor gene expression) and deacefylases (favor inactive chromatin)... 

Woodcock, C.L.F. (1973) Ultrastructure of inactive chromatin. J. Cell Biol. 59, 368a. 

In contrast to this, inactive chromatin is characterized by histone hypoacetylation and the enrichment of histone H3 lysine 9 (H3/K9) methylation [6]. 

Fig. 1.40. Model of repression and activation of transcription. The figure illustrates various mechanisms of repression of transcription, a) genes are in a generally repressed states in inactive chromatin. In a first phase of activation the chromatin is restrnctured. b) The promoter is now accessible for the binding of the basal transcription factors and for RNA polymerase II. c) An initiation complex is formed that contains the central components of the transcription apparatns, bnt which enables transcription only at a low rate, d) the binding of repressors to the transcription initiation complex can prevent fnrther activation of transcription at this step, e) the binding of transcription activators to their DNA elements leads to activation of transcription, f) an active repression is affected by proteins that bind seqnence specifically to DNA elements and in their DNA-bound form inhibit the transcritption preventing interactions with the transcription apparatus.

Transcriptionally Active Chromatin Is Structurally Distinct from Inactive Chromatin... 

Biochemical Differences between Active and Inactive, Chromatin... 

Much of the preceding discussion on chromatin structure indicates that active chromatin exists in a more swollen state than inactive chromatin. Several biochemical changes accompany the transition from condensed to swollen chromatin. These changes include a redistribution of nucleosomes along the DNA duplex, chemical modification of histones, alteration in the pattern of nonhistone chromosomal protein binding, and chemical modification of the DNA. Currently, most of these changes are discussed in a general, descriptive manner because their causes and consequences are not known. 

List some characteristics that distinguish active from inactive chromatin. 

The discovery of the involvement of a transcription factor in excision repair was prompted by the observation by Bohr et al. (1985) that excision-repair was differentiated between fast repair coupled with transcription and a slower mode observed in non-transcribing regions of DNA. One of the human genes, XPC, is required only for the latter mode of repair. Its homologue, RAD4 in yeast, where similar differentiation has been observed, is found to associate with the TFIIH complex, suggesting that these proteins may be involved in associating the complex specifically with inactive chromatin. 

As discussed, histones are an integral part of nucleo-somes, the basic repeating structural unit of chromatin. The amino termini of histone proteins can be modified post-translationally by processes that include acetylation, methylation, phosphorylation, and ubiquination. Acetylation of the lysines on the amino termini of histones H3 and H4 by histone acetyltransferases decreases histone-DNA interaction and improves the accessibility of DNA to transcriptional activation. On the contrary, histone deacetylation by histone deacetylases promotes the formation of compact nucleo-somes, leading to repression of transcription. Histone deacetylation is in fact a key component to the assembly of heterochromatin, the transcriptionally inactive chromatin. Methylation of the ninth amino acid residue, lysine, on histone H3 generates a binding site for heterochromatin protein (HP 1) and thus is another key event in heterochromatin formation. Phosphorylation of the tenth amino acid, serine, on histone H3 is important for chromosome condensation and mitosis. 

Hypoacetylated, transcriptionally inactive chromatin assumes a more condensed structure and is more resistant to DNase I than hyperacetylated, transcriptionally active chromatin. 

Oer>e po r chrcHDOsorTW ragJons G ne>f>oor transchptl ndtly Inactive chromatin... 

Kass SU, Goddard JP, Adams RLP. Inactive chromatin spreads from a focus of methylation. Mol Cell Biol 1993 13 7372-7379. 

Remarkably, the highest concentration of hyaluronan in cells is found in the chromato-spherite in the vicinity of the nucleus membrane [51]. Specifically, chromatin in the vicinity of a nuclear membrane is composed of the most condensed form of inactive chromatin with chromosomes that are connected with the internal surface of the nuclear membrane. A high degree of chromosome organization is preserved in the interphase nucleus of differentiated cells [117]. The centromeres of chromosomes are grouped and associated with the nuclear membrane on one side of the nucleus, whereas telomeres (end-sections of chromosomes) are connected with the membrane on another side. (Figure 2.10). 

Whether a gene is positioned in active or inactive chromatin certainly also plays a large role in whether or not transcription can occur. The various elements which define active chromatin (sensitivity and hypersensitivity to nucleases, presence of HMG proteins, modifications of both histone and nonhistone chromosomal proteins, DNA methylation) have recently been reviewed (Weisbrod, 1982 Razin and Riggs, 1980). With a few exceptions, there is no clear idea how the DNA sequences and proteins which are known to modulate transcription relate to the formation of active chromatin. Such a discussion must therefore be deferred to a later date. 

Woodcock, C. L. F., 1973, Ultrastructure of inactive chromatin, J. Cell Biol. 59 368a. Yoshihara, K., Tanigawa, Y., Burzio, L., and Koide, S. S., 1975, Evidence for adenosine diphosphate ribosylation of Ca , Mg -dependent endonuclease, Proc. Natl. Acad. Sci. USA 72 289. 

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