David Landsman

A Genome-Wide Transcriptional Analysis of the Mitotic Cell Cycle

Progression through the eukaryotic cell cycle is known to be both regulated and accompanied by periodic fluctuation in the expression levels of numerous genes. We report here the genome-wide characterization of mRNA transcript levels during the cell cycle of the budding yeast S. cerevisiae. Cell cycle-dependent periodicity was found for 416 of the 6220 monitored transcripts. More than 25% of the 416 genes were found directly adjacent to other genes in the genome that displayed induction in the same cell cycle phase, suggesting a mechanism for local chromosomal organization in global mRNA regulation. More than 60% of the characterized genes that displayed mRNA fluctuation have already been implicated in cell cycle period-specific biological roles. Because more than 20% of human proteins display significant homology to yeast proteins, these results also link a range of human genes to cell cycle period-specific biological functions.

Structural features of the HMG chromosomal proteins and their genes.

I Laboratory of Molecular Carcinogenesis, National Cancer Institute and 2 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD (U.S.A.) (Received 30 March 1990) Key words: Chromosomal protein; Chromatin structure; Gene structure; DNA-protein interaction; High mobility group protein

High-resolution genome-wide mapping of histone modifications

The expression patterns of eukaryotic genomes are controlled by their chromatin structure, consisting of nucleosome subunits in which DNA of approximately 146 bp is wrapped around a core of 8 histone molecules. Post-translational histone modifications play an essential role in modifying chromatin structure. Here we apply a combination of SAGE and chromatin immunoprecipitation (ChIP) protocols to determine the distribution of hyperacetylated histones H3 and H4 in the Saccharomyces cerevisiae genome. We call this approach genome-wide mapping technique (GMAT). Using GMAT, we find that the highest acetylation levels are detected in the 5′ end of a genes coding region, but not in the promoter. Furthermore, we show that the histone acetyltransferase, GCN5p, regulates H3 acetylation in the promoter and 5′ end of the coding regions. These findings indicate that GMAT should find valuable applications in mapping target sites of chromatin-modifying enzymes.

A unified phylogeny-based nomenclature for histone variants

Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.

Histone structure and nucleosome stability

Histone proteins play essential structural and functional roles in the transition between active and inactive chromatin states. Although histones have a high degree of conservation due to constraints to maintain the overall structure of the nucleosomal octameric core, variants have evolved to assume diverse roles in gene regulation and epigenetic silencing. Histone variants, post-translational modifications and interactions with chromatin remodeling complexes influence DNA replication, transcription, repair and recombination. The authors review recent findings on the structure of chromatin that confirm previous interparticle interactions observed in crystal structures.

Learning about addiction from the genome

Drug addiction can be defined as the compulsive seeking and taking of a drug despite adverse consequences. Although addiction involves many psychological and social factors, it also represents a biological process: the effects of repeated drug exposure on a vulnerable brain. The sequencing of the human and other mammalian genomes will help us to understand the biology of addiction by enabling us to identify both genes that contribute to individual risk for addiction and those through which drugs cause addiction. We illustrate this potential impact by searching a draft sequence of the human genome for genes related to desensitization of receptors that mediate the actions of drugs of abuse on the nervous system.

Towards BioDBcore: a community-defined information specification for biological databases

The present article proposes the adoption of a community-defined, uniform, generic description of the core attributes of biological databases, BioDBCore. The goals of these attributes are to provide a general overview of the database landscape, to encourage consistency and interoperability between resources; and to promote the use of semantic and syntactic standards. BioDBCore will make it easier for users to evaluate the scope and relevance of available resources. This new resource will increase the collective impact of the information present in biological databases.

The Histone Database

Histone proteins are often noted for their high degree of sequence conservation. It is less often recognized that the histones are a heterogeneous protein family. Furthermore, several classes of non-histone proteins containing the histone fold motif exist. Novel histone and histone fold protein sequences continue to be added to public databases every year. The Histone Database (http://genome.nhgri.nih.gov/histones/) is a searchable, periodically updated collection of histone fold-containing sequences derived from sequence-similarity searches of public databases. Sequence sets are presented in redundant and non-redundant FASTA form, hotlinked to GenBank sequence files. Partial sequences are also now included in the database, which has considerably augmented its taxonomic coverage. Annotated alignments of full-length non-redundant sets of sequences are now available in both web-viewable (HTML) and downloadable (PDF) formats. The database also provides summaries of current information on solved histone fold structures, post-translational modifications of histones, and the human histone gene complement.

Evolutionary rates and patterns for human transcription factor binding sites derived from repetitive DNA

BackgroundThe majority of human non-protein-coding DNA is made up of repetitive sequences, mainly transposable elements (TEs). It is becoming increasingly apparent that many of these repetitive DNA sequence elements encode gene regulatory functions. This fact has important evolutionary implications, since repetitive DNA is the most dynamic part of the genome. We set out to assess the evolutionary rate and pattern of experimentally characterized human transcription factor binding sites (TFBS) that are derived from repetitive versus non-repetitive DNA to test whether repeat-derived TFBS are in fact rapidly evolving. We also evaluated the position-specific patterns of variation among TFBS to look for signs of functional constraint on TFBS derived from repetitive and non-repetitive DNA.ResultsWe found numerous experimentally characterized TFBS in the human genome, 7–10% of all mapped sites, which are derived from repetitive DNA sequences including simple sequence repeats (SSRs) and TEs. TE-derived TFBS sequences are far less conserved between species than TFBS derived from SSRs and non-repetitive DNA. Despite their rapid evolution, several lines of evidence indicate that TE-derived TFBS are functionally constrained. First of all, ancient TE families, such as MIR and L2, are enriched for TFBS relative to younger families like Alu and L1. Secondly, functionally important positions in TE-derived TFBS, specifically those residues thought to physically interact with their cognate protein binding factors (TF), are more evolutionarily conserved than adjacent TFBS positions. Finally, TE-derived TFBS show position-specific patterns of sequence variation that are highly distinct from random patterns and similar to the variation seen for non-repeat derived sequences of the same TFBS.ConclusionThe abundance of experimentally characterized human TFBS that are derived from repetitive DNA speaks to the substantial regulatory effects that this class of sequence has on the human genome. The unique evolutionary properties of repeat-derived TFBS are perhaps even more intriguing. TE-derived TFBS in particular, while clearly functionally constrained, evolve extremely rapidly relative to non-repeat derived sites. Such rapidly evolving TFBS are likely to confer species-specific regulatory phenotypes, i.e. divergent expression patterns, on the human evolutionary lineage. This result has practical implications with respect to the widespread use of evolutionary conservation as a surrogate for functionally relevant non-coding DNA. Most TE-derived TFBS would be missed using the kinds of sequence conservation-based screens, such as phylogenetic footprinting, that are used to help characterize non-coding DNA. Thus, the very TFBS that are most likely to yield human-specific characteristics will be neglected by the comparative genomic techniques that are currently de rigeur for the identification of novel regulatory sites.

The histone database : A comprehensive resource for histones and histone fold-containing proteins

TheThe Histone Database is a curated and searchable collection of full‐length sequences and structures of histones and nonhistone proteins containing histone‐like folds, compiled from major public databases. Several new histone fold‐containing proteins have been identified, including the huntingtin‐interacting protein HYPM. Additionally, based on the recent crystal structure of the Son of Sevenless protein, an interpretation of the sequence analysis of the histone fold domain is presented. The database contains an updated collection of multiple sequence alignments for the four core histones (H2A, H2B, H3, and H4) and the linker histones (H1/H5) from a total of 975 organisms. The database also contains information on the human histone gene complement and provides links to three‐dimensional structures of histone and histone fold‐containing proteins. The Histone Database is a comprehensive bioinformatics resource for the study of structure and function of histones and histone fold‐containing proteins. The database is available at http://research.nhgri.nih.gov/histones/. Proteins 2006.