Histone acetylation in gene regulation.

Genetic information is packaged in the highly dynamic nucleoprotein structure called chromatin. Many biological processes are regulated via post-translational modifications of key proteins. Acetylation of lysine residues at the N-terminal histone tails is one of the most studied covalent modifications influencing gene regulation in eukaryotic cells. This review focuses on the role of enzymes involved in controlling both histone and non-histone proteins acetylation levels in the cell, with particular emphasis on their effects on cancer.     

酿酒酵母组蛋白乙酰化修饰及其对基因表达的调控

真核生物核小体组蛋白修饰引起染色质重塑(Chromatin remodeling)是表观遗传的重要调控机制.乙酰化修饰(Acetylation modification)是其中一种重要的方式.组蛋白乙酰化修饰位点集中在各种组蛋白N末端赖氨酸残基上.细胞内存在功能拮抗的多种乙酰基转移酶和去乙酰化酶,二者相互竞争,共同调节组蛋白的乙酰化状态,通过影响核小体结构的致密性,并在多种效应分子的参与下,实现对基因的表达调控.以真核模式生物酿酒酵母(Saccharomyces cerevisiae)为对象,综述乙酰基转移酶和去乙酰化酶的种类、作用特点以及其基因调控的分子机制等方面的最新研究进展.     

The relationship between gene dosage,gene expression,and sex in Drosophila

In Drosophila, the ratio of the number of X chromosomes to sets of other chromosomes initiates a series of events which result in sexual differentiation. In addition, this ratio establishes dosage compensation, a mechanism which equalizes the products of X-linked genes in males and females. The present review discusses possible genetic entities responsible for the interpretation of chromosomal sex and subsequent sex-mediated regulation during development.     

Histone acetylation in drug addiction

Regulation of chromatin structure through post-translational modifications of histones (e.g., acetylation) has emerged as an important mechanism to translate a variety of environmental stimuli, including drugs of abuse, into specific changes in gene expression. Since alterations in gene expression are thought to contribute to the development and maintenance of the addicted state, recent efforts are aimed at identifying how drugs of abuse alter chromatin structure and the enzymes which regulate it. This review discusses how drugs of abuse alter histone acetylation in brain reward regions, through which enzymes this occurs, and ultimately what role histone acetylation plays in addiction-related behaviors.     

Histone acetylation and X inactivation

In mammals, the levels of X-linked gene products in males and females are equalised by the silencing, early in development, of most of the genes on one of the two female X chromosomes. Once established, the silent state is stable from one cell generation to the next. In eutherian mammals, the inactive X chromosome (Xi) differs from its active homologue (Xa) in a number of ways, including increased methylation of selected CpGs, replication late in S-phase, expression of the Xistgene with binding of Xist RNA and underacetylation of core histones. The latter is a common property of genetically inactive chromatin but, in the case of Xi, it is not clear whether it is an integral part of the silencing process or simply a consequence of some other property of Xi, such as late replication. The present review describes two approaches that address this problem. The first shows that Xi in marsupial mammals also contains underacetylated H4, even though its properties differ widely from those of the eutherian Xi. The continued presence of histone underacetylation on Xi in these evolutionarily distant mammals argues for its fundamental importance. The second approach uses mouse embryonic stem cells and places H4 deacetylation in a sequence of events leading to complete X inactivation. The results argue that histone underacetylation plays a role in the stabilisation of the inactive state, rather than in its initiation. Dev. Genet. 22:65–73, 1998. © 1998 Wiley-Liss, Inc.     

Histone acetylation and cancer.

In the past year, several papers have been published which implicate a link between alterations in chromatin structure and the development of cancer. Both histone hyperacetylation and hypoacetylation appear to be important in the neoplastic process, depending on the target gene involved. In the case of colon cancer, induction of the p21 gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis.     

Design and utility of temperature-sensitive Gal4 mutants for conditional gene expression in Drosophila

Temperature-sensitive (ts) mutants are valuable tools to study the function of essential genes in vivo. Despite their widespread use, little is known about mechanisms responsible for the temperature-sensitive (ts) phenotype, or of the transferability of ts mutants of a specific gene between organisms. Since ts mutants are typically generated by random mutagenesis it is difficult to isolate such mutants without efficient screening procedures. We have recently shown that it is possible to obtain ts mutants at high frequency by targeted mutations at either predicted, buried residues important for protein stability or at functional, ligand binding residues. The former class of residues can be identified solely from amino acid sequence and the latter from Ala scanning mutagenesis or from a structure of the protein:ligand complex. Several ts mutants of Gal4 in yeast were generated by mutating both categories of residues. Two of these ts mutants were also shown to result in tight and rapid ts reporter gene-expression in Drosophila when driven by either the elav or GMR promoters. We suggest possible mechanisms that might be responsible for such transferable ts phenotypes and also discuss some of the limitations and difficulties involved in rational design of ts mutants.     

Histone acetylation and the deoxyribonuclease I sensitivity of the Tetrahymena ribosomal gene

Under appropriate conditions, up to 8.5% of the total acetate can be removed from the histones of isolated Tetrahymena macronuclei by an endogenous histone deacetylase activity. After in vitro deacetylation, the ribosomal genes are still preferentially digested by DNase I. These observations suggested that either the majority of histone-bound acetate is unnecessary to maintain the DNase I sensitive state or ribosomal chromatin (rChromatin) histones remain acetylated under these conditions. The characteristics of histones acetylation were studied in Tetrahymena rChromatin, which can be isolated in a relatively pure form. Histones associated with the presumably active, DNase I sensitive ribosomal genes have a high steady-state level of histone acetylation which, surprisingly, is maintained by very low acetate turnover rates.