Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.

/pdf/regulation-of-chromatin-by-histone-modifications-35b8poynlc.pdf

Regulation of chromatin by histone modifications

Cancer epigenetics: from mechanism to therapy.

Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.

/pdf/histone-deacetylase-inhibitors-and-the-promise-of-epigenetic-lebszxehof.pdf

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A.

More than 30 years ago, Vincent Allfrey proposed that histone acetylation was associated with transcriptional activity in eukaryotic cells (Allfrey et al. 1964; Pogo et al. 1966). Subsequently, acetylated core histones were shown to preferentially associate with transcriptionally active chromatin (Sealy and Chalkley 1978; Vidali et al. 1978; Hebbes et al. 1988). Acetylation occurs at lysine residues on the amino-terminal tails of the histones, thereby neutralizing the positive charge of the histone tails and decreasing their affinity for DNA (Hong et al. 1993). As a consequence, histone acetylation alters nucleosomal conformation (Norton et al. 1989), which can increase the accessibility of transcriptional regulatory proteins to chromatin templates (Lee et al. 1993; Vettese-Dadey et al. 1996). Taken together, these observations suggested how histone acetylation could result in increased transcriptional activity in vivo. However, there was essentially no information about the cause and effect relationship between histone acetylation and transcriptional activity or about the underlying molecular mechanisms. A mechanistic and physiologically relevant connection between histone acetylation and transcriptional regulation was initially provided by two independent lines of evidence. First, yeast cells unable to acetylate the histone H4 tail because of mutations of the target lysine residues show altered patterns of transcription (Durrin et al. 1991). However, these mutations broadly affect chromatin structure in vivo, and hence are likely to influence other molecular processes involving DNA (e.g., DNA replication and repair, recombination, chromosome segregation). Second, treatment of mammalian cells with potent inhibitors of histone deacetylase activity such as trapoxin or trichostatin A resulted in increased expression of a variety of genes (Yoshida et al. 1995). However, these drugs might inhibit other cellular targets, and they affect a variety of cellular processes, including cell proliferation, apoptosis, differentiation, and DNA synthesis. Although these observations were suggestive, understanding of the relationship between chromatin structure and transcription regulation was hampered significantly by a lack of knowledge about the enzymes that acetylate and deacetylate histones. In the past 2 years, our understanding of the causal relationship between histone acetylation and gene expression has been enhanced dramatically by the identification of proteins with intrinsic histone acetylase and deacetylase activity (Brownell et al. 1996; for recent reviews, see Grunstein 1997; Pazin and Kadonaga 1997; Wade et al. 1997). Of particular significance, some of these enzymes had been identified previously as components of the RNA polymerase II (Pol II) transcription machinery itself, proteins that associate with transcriptional regulatory factors, or proteins that positively or negatively affect transcription in vivo. These discoveries have led to a major paradigm shift. It is now clear that chromatin structure and modification can not be viewed as a process that is independent of transcriptional initiation, that is, chromatin is not simply a structure that serves to compact DNA in the nucleus and provide a relatively passive substrate for the action of transcription factors. Instead, histone acetylases and deacetylases provide a critical link between chromatin structure and transcriptional output, and this link is now accessible to experimental intervention. This review will focus on molecular mechanisms by which histone acetylation affects transcriptional activity in living cells.

/pdf/histone-acetylation-and-transcriptional-regulatory-4n090msahh.pdf

Histone acetylation and transcriptional regulatory mechanisms

17 Ohno, S., and B. M. Cattanach, Cytogenet., 1, 129 (1962). 18 Russell, L. B., Science, 140, 976 (1963). 19 Lyon, M. F., Genetic Res., 4, 93 (1963). *' Benirschke, K., R. J. Low, L. E. Brownhill, L. B. Caday, and J. deVenecia-Fernandez, Chromosoma, in press. 21 Davidson, R. G., H. M. Nitowsky, and B. Childs, these PROCEEDINGS, 50, 481 (1963). 22Beutler, E., and M. Baluda, Lancet, I, 189 (1964). 23 Bach, F., and K. Hirschhorn, Proc. 11th Intern. Congr. Genet., p. 312 (1963). 24Sanger, R., R. R. Race, P. Tippett, J. Hamper, J. Gavin, and T. E. Cleghorn, Vox Sang., 7, 571 (1962) 2 Gorman, J. G., A. M. Treacy, and A. Cahan, J. Lab. Clin. Med., 61, 642 (1963). 26Reed, T. E., N. E. Simpson, and B. Chown, Lancet, H, 467 (1963). 27 Lindsten, J., M. Fraccaro, P. E. Polani, J. L. Hamerton, R. Sanger, and R. R. Race, Nature, 197, 648 (1963). '\" Muldal, S., L. Tiepolo, M. Fraccaro, and J. Lindsten, unpublished data.

https://www.pnas.org/content/pnas/51/5/786.full.pdf

A. E. Mirsky

Papers

Acetylation and methylation of histones and their possible role in the regulation of rna synthesis

An estimate of the catalytic-centre activity and purity of human alkaline phosphatase preparations