Chromatin changes

Despite all these well-established functional implications, the structural involvement of this chemical modification in the chromatin changes involved in these processes has remained largely elusive [29]. 

As described recently in an editorial entitled How Chromatin Changes Its Shape (Hagmann, 1999), many of the coactivators and proteins known to be involved in ER action are also key factors in the control of gene activity by a long series of nonhormonal cell modulators. Clearly, the mechanism of action of ER is central to the control of cell function in a long series of tissues that play essential roles in reproduction and thus permit the continuation of human life. 

M. Hagmann. How chromatin changes its shape. News Focus. Science, 285, 1200-1203, 1999. 

Hotz, M. A., Gong, J., Traganos, F., and Darzynkiewicz, Z. (1994) Flow cytometric detection of apoptosis comparison of the assays of in situ DNA degradation and chromatin changes. Cytometry 15(3), 237-244. 

Much remains to be learned about the structure of chromatin and how that structure influences transcription. What directs certain regions of chromatin to form heterochromatin where transcription is repressed Precisely how Is the structure of chromatin changed by activators and repressors and how does this promote or inhibit transcription Once chromatin-remodeling complexes and histone acetylase complexes become associated with a promoter region, how do they remain associated Do certain subunits of these complexes associate with modified histone tails so that additional complexes associate along the length of a chromatin fiber as additional histones are modified ... 

Rb family members may also regulate gene expression by affecting chromatin structure. These chromatin changes are invoked by the recruitment of histone deacetylases (HDACs), histone methyltransferases, SWI/SNF complex members, and, less well-characterized DNA methyltransferases and polycomb proteins (Jackson and Pereira-Smith 2006). The integrity of the Rb pathway can influence the activity of p53 and vice versa (Hsieh et al. 2002). 

In the case of liganded NRs, ligand binding is the first and ciucial molecular event that switches the function of these transcription factors from inactive to active state by inducing a conformational change in the LBD of the receptor (Fig. 1). This specific conformation allows the second step of NR activation that corresponds to the recruitment of coregulatoiy complexes, which contain chromatin-modifying enzymes required for transcription. The transcriptional coactivators are very diverse and have expanded to more than hundred in number. These include the pi 60 family of proteins,... 

All steps—from changes in DNA template, sequence, and accessibility in chromatin to RNA stability—are subject to modulation and hence are potential control sites for eukaryotic gene regulation. 

Finally, the binding of specific transcription factors to cognate DNA elements may result in disruption of nucleosomal structure. Many eukaryotic genes have multiple protein-binding DNA elements. The serial binding of transcription factors to these elements—in a combinatorial fashion—may either directly disrupt the structure of the nucleosome or prevent its re-formation or recruit, via protein-protein interactions, multiprotein coactivator complexes that have the ability to covalently modify or remodel nucleosomes. These reactions result in chromatin-level structural changes that in the end increase DNA accessibifity to other factors and the transcription machinery. 

An additional question relating to sites of modification is the possible influence of DNA binding proteins and the conformational changes they induce in DNA as it forms chromatin, which in turn may influence available binding sites for adduct formation. Several studies have investigated the distribution of DNA adducts in chromatin (95-102). although no clear answer for the influence of these proteins has yet emerged. 

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