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

Histone acetylation regulates many cellular processes, and specific acetylation marks, either singly or in combination, produce distinct outcomes. For example, the acetylation pattern on newly synthesized histones is important for their assembly into nucleosomes by histone chaperones. Additionally, the degree of chromatin compaction and folding may be regulated by acetylation of histone H4 at lysine 16. Histone acetylation also regulates the formation of heterochromatin; deacetylation of H4 lysine 16 is important for spreading of heterochromatin components, whereas acetylation of this site serves as a barrier to this spreading. Finally, histone acetylation is critical for gene transcription, but recent results suggest that deacetylation of certain sites also plays an important role. There are many histone acetyltransferases (HATs) and deacetylases, with differing preferences for the various histone proteins and for specific sites on individual histones. Determining how these enzymes create distinc...

Functions of site-specific histone acetylation and deacetylation.

The enzyme-catalyzed acetylation of the N-terminal tail domains of core histones provides a rich potential source of epigenetic information. This may be used both to mediate transient changes in transcription, through modification of promoter-proximal nucleosomes, and for the longer-term maintenance and modulation of patterns of gene expression. The latter may be achieved by setting specific patterns of histone acetylation, perhaps involving acetylation of particular lysine residues, across relatively large chromatin domains. The histone acetylating and deacetylating enzymes (HATs and HDACs, respectively) can be targeted to specific regions of the genome and show varying degrees of substrate specificity, properties that are consistent with a role in maintaining a dynamic, acetylation-based epigenetic code. The code may be read (ie. exert a functional effect) either through non-histone proteins that bind in an acetylation-dependent manner, or through direct effects on chromatin structure. Recent evidence raises the interesting possibility that an acetylation-based code may operate through both mitosis and meiosis, providing a possible mechanism for germ-line transmission of epigenetic changes.

Histone acetylation and an epigenetic code

The nucleosome, which is the primary building block of chromatin, is not a static structure: It can adopt alternative conformations. Changes in solution conditions or changes in histone acetylation state cause nucleosomes and nucleosomal arrays to behave with altered biophysical properties. Distinct subpopulations of nucleosomes isolated from cells have chromatographic properties and nuclease sensitivity different from those of bulk nucleosomes. Recently, proteins that were initially identified as necessary for transcriptional regulation have been shown to alter nucleosomal structure. These proteins are found in three types of multiprotein complexes that can acetylate nucleosomes, deacetylate nucleosomes, or alter nucleosome structure in an ATP-dependent manner. The direct modification of nucleosome structure by these complexes is likely to play a central role in appropriate regulation of eukaryotic genes.

Alteration of Nucleosome Structure as a Mechanism of Transcriptional Regulation

https://www.cell.com/cell/pdf/0092-8674(78)90305-7.pdf

Sodium butyrate inhibits histone deacetylation in cultured cells

Modifications to histones immediately after synthesis

Studies on highly metabolically active acetylation and phosphorylation of histones.

A cysteine-containing H2B-like histone found in mature mammalian testis.

Two new histones have been found in sexually mature testes of several mammals. The new histones have been identified as a new F1 (TF1) and F2b (TF2b) on the basis of their behavior upon chemical fractionation procedures and electrophoresis at several urea concentrations. The new testis-specific histones are absent in very immature animals and in somatic tissues. However, by day 20, in the rat, the histone pattern is that of the adult, displaying nearly a full complement of TF1 and TF2b. The new histone complement evidently is characteristic of prespermatid germ cells. The degree of evolutionary variations in these histones and in other basic sperm proteins, as detected by change in electrophoretic mobility, appears to be much greater than that seen in somatic histones.

https://www.pnas.org/content/pnas/72/7/2714.full.pdf

New histones found in mature mammalian testes

http://www.jbc.org/content/257/10/5809.full.pdf

A Shires

Papers

Modifications to histones immediately after synthesis

Studies on highly metabolically active acetylation and phosphorylation of histones.

A cysteine-containing H2B-like histone found in mature mammalian testis.

New histones found in mature mammalian testes

Histone hypoacetylation following release of HTC cells from butyrate.