It is more evident now than ever that nucleosomes can transmit epigenetic information from one cell generation to the next. It has been demonstrated during the past decade that the posttranslational modifications of histone proteins within the chromosome impact chromatin structure, gene transcription, and epigenetic information. Multiple modifications decorate each histone tail within the nucleosome, including some amino acids that can be modified in several different ways. Covalent modifications of histone tails known thus far include acetylation, phosphorylation, sumoylation, ubiquitination, and methylation. A large body of experimental evidence compiled during the past several years has demonstrated the impact of histone acetylation on transcriptional control. Although histone modification by methylation and ubiquitination was discovered long ago, it was only recently that functional roles for these modifications in transcriptional regulation began to surface. Highlighted in this review are the recent biochemical, molecular, cellular, and physiological functions of histone methylation and ubiquitination involved in the regulation of gene expression as determined by a combination of enzymological, structural, and genetic methodologies.

Chromatin Modifications by Methylation and Ubiquitination: Implications in the Regulation of Gene Expression

http://idv.sinica.edu.tw/ckao/paper/Lab%20meeting/H3%20K79me-Dot1-Gottschling-Cell-2002.pdf

Dot1p Modulates Silencing in Yeast by Methylation of the Nucleosome Core

Methylation of H3-Lysine 79 Is Mediated by a New Family of HMTases without a SET Domain

▪ Abstract Genomes are organized into active regions known as euchromatin and inactive regions known as heterochromatin, or silenced chromatin. This review describes contemporary knowledge and models for how silenced chromatin in Saccharomyces cerevisiae forms, functions, and is inherited. In S. cerevisiae, Sir proteins are the key structural components of silenced chromatin. Sir proteins interact first with silencers, which dictate which regions are silenced, and then with histone tails in nucleosomes as the Sir proteins spread from silencers along chromosomes. Importantly, the spreading of silenced chromatin requires the histone deacetylase activity of Sir2p. This requirement leads to a general model for the spreading and inheritance of silenced chromatin or other special chromatin states. Such chromatin domains are marked by modifications of the nucleosomes or DNA, and this mark is able to recruit an enzyme that makes further marks. Thus, among different organisms, multiple forms of repressive chromati...

The Establishment, Inheritance, and Function of Silenced Chromatin in Saccharomyces cerevisiae

Histone modifications are key epigenetic regulatory features that have important roles in many cellular events. Lysine methylations mark various sites on the tail and globular domains of histones and their levels are precisely balanced by the action of methyltransferases (‘writers’) and demethylases (‘erasers’). In addition, distinct effector proteins (‘readers’) recognize specific methyl-lysines in a manner that depends on the neighboring amino-acid sequence and methylation state. Misregulation of histone lysine methylation has been implicated in several cancers and developmental defects. Therefore, histone lysine methylation has been considered a potential therapeutic target, and clinical trials of several inhibitors of this process have shown promising results. A more detailed understanding of histone lysine methylation is necessary for elucidating complex biological processes and, ultimately, for developing and improving disease treatments. This review summarizes enzymes responsible for histone lysine methylation and demethylation and how histone lysine methylation contributes to various biological processes. Elucidating how enzymes add and subtract methyl groups to the proteins that package DNA could lead to new disease treatments. In a review article, Jaehoon Kim and colleagues from the Korea Advanced Institute of Science and Technology in Daejeon, South Korea, summarize the mechanisms by which histone proteins, which assemble to form spool-like complexes around which DNA wraps into more compact units, are modified and how misregulation of this process can lead to cancer, developmental defects and other health problems. The authors focus on how methyl groups are added to and removed from residues of the amino acid lysine within histone proteins. They liken certain enzymes to writers, erasers and readers of histone lysine methylation, and make the case that these enzymes should be investigated as potential therapeutic targets.

/pdf/writing-erasing-and-reading-histone-lysine-methylations-3rnlvgubc1.pdf

Writing, erasing and reading histone lysine methylations

The ends of chromosomes in Saccharomyces cerevisiae initiate a repressive chromatin structure that spreads internally and inhibits the transcription of nearby genes, a phenomenon termed telomeric silencing. To investigate the molecular basis of this process, we carried out a genetic screen to identify genes whose overexpression disrupts telomeric silencing. We thus isolated 10 DOT genes (disruptor of telomeric silencing). Among these were genes encoding chromatin component Sir4p, DNA helicase Dna2p, ribosomal protein L32, and two proteins of unknown function, Asf1p and Ifh1p. The collection also included genes that had not previously been identified: DOT1, DOT4, DOT5, DOT6, and TLC1, which encodes the RNA template component of telomerase. With the exception of TLC1, all these genes, particularly DOT1 and DOT4, also reduced silencing at other repressed loci (HM loci and rDNA) when overexpressed. Moreover, deletion of the latter two genes weakened silencing as well, suggesting that DOT1 and DOT4 normally play important roles in gene repression. DOT1 deletion also affected telomere tract length. The function of Dot1p is not known. The sequence of Dot4p suggests that it is a ubiquitin-processing protease. Taken together, the DOT genes include both components and regulators of silent chromatin.

https://www.genetics.org/content/genetics/150/2/613.full.pdf

Maureen Mahowald

Papers

Identification of High-Copy Disruptors of Telomeric Silencing in Saccharomyces cerevisiae