Chromatin transcriptional activity

Closed chromatin trascriptional repression Open chromatin transcriptional activation... 

It is possible that the protein receptors which recognize the inducer substances and hormones and which determine the tissue competence are synthesized in this period, also. It is known, for instance, that in the differentiating embryonic and regenerating liver more RNA types are synthesized than are necessary for specialized mature cell. In the early period of the liver cell specialization there is a surplus of the RNA templates (Church and McCarthy, 1967). There are data that changing of the RNA amount is accompanied by the oscillation of the chromatin transcriptional activity (Thaler and Villee, 1967). Thus, the cell during development is as if... 

Coactivators enhancing the transcriptional activity of steroid hormone receptors activators include SRC-1 (steroid-receptor co-activator 1) or TEF2 (transcriptional intermediary factor 2), which are recruited by the DNA/ steroid hormone receptor complex. Their main role is to attract other transcriptional coactivators with histone acetyltransferase activity in order to decondense chromatin and allow for the binding of components of the general transcription apparatus. 

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

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). 

One of the most-studied covalent modifications is the acetylation of the lysine residues of histone tails. The acetylation state of lysines of nucleosomal histones modulates chromatin structure and regulates gene transcriptional activity. The balance of lysine acetylation is controlled by the antagonistic action of two enzyme families histone deacetylases (HDACs) and histone acetyltransferases (HATs). In humans there are essentially three main HDAC subclasses [6]. 

Regulating mono-ubiquitination of proteins by DUBs is important in histone modification where ubiquitination is thought to modulate chromatin structure and transcriptional activity. Normally, about 10% of the histone core octomers contain ubiquitinated histones and the ubiquitin is removed at mitosis by DUB activity. UBP8 has been demonstrated to regulate the ubiquitination of histone H2B, which is important in transcriptional activation of many genes [88]. 

A system such as this can provide a powerful mechanism for transcriptional control. While bound to nucleosomes, PARP-1 promotes a transcriptionally repressed state, but one that is simultaneously poised for activation because of the allosteric activating effect of nucleosomes on PARP-1 enzymatic activity. In the presence of NAD+, PARP-1 can autoPARylate and release from nucleosomes, shifting the chromatin to a more transcriptionally active conformation. PARC can reset the system by cleaving the PAR chains from PARP-1, allowing PARP-1 to re-bind the nucleosomes and re-establish a transcriptionally repressed state. 

As expected, in vitro transcription assays involving PARP-1, NAD, and PARC illustrate these predicted outcomes (Kim et al, 2004). Even when driven by a transcriptional activator, such as estradiol-bound estrogen receptor, transcription is repressed when PARP-1 is added to chromatin templates. The repression is reversed by NAD+, and the NAD+-dependent effects are reversed by PARC (Kim et al, 2004). This system for transcriptional control shifts new importance onto the enzymes responsible for synthesis of NAD+ in the nucleus, such as nicotinamide mononucleotide adenylyltransferase-1 (Magni et al, 2004). Because NAD+ facilitates the decompaction of chromatin and the derepression of transcription, nuclear NAD+ biosynthetic enzymes may play critical roles as cofactors. 

Abbott DW, Ivanova VS, Wang X, Bonner WM, Ausio J (2001) Characterization of the stability and folding of H2A.Z chromatin particles implications for transcriptional activation. J Biol Chem 276 41945 1949... 

Figure 2. Histone chaperones facilitate favorable chromatin dynamics during transcriptional activation Transcriptional competence of chromatin template is achieved by die replacement of histone variants and finally removal of histones. Histone chaperone may help in bodi die process in a replication independent manner. Acetylation of histone and also die chaperone may assist in diis process. Recent evidence suggest that NPMl may participate in these events globally or gene specific manner. (See Colour Plate 11.)...

Figure 3. (a) Scheme of transcription, (b) Histone chaperone nucleophosmin/NPMl enhance acetylation dependent chromatin transcription NPMl stimulates chromatin transcription in a dose dependent manner. Lane 1,without activator lanes 2-6, with the activator Gal-VP16 (50 ng) lanes 3-6, with p300 (25 ng) lanes 4-6, with acetyl CoA (1.5 pM) lane 5, 1 pmol, lane 6, 10 pmols of full length NPMl... 

These different reports indicate that nucleolin could influence transcription positively or negatively. These seemingly contradictory data might be explained if one considers that nucleolin does not act as a real transcriptional activator or repressor, but rather indirectly through the regulation of chromatin structure. 

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