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D Landsman

Publications and source records attributed to D Landsman.

At least 19 recordsLinked to original sources
PubMed2007

TLX1/HOX11-induced hematopoietic differentiation blockade.

Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.

Acetylation↗
PubMed2005

Transposable elements donate lineage-specific regulatory sequences to host genomes.

The evolutionary implications of transposable element (TE) influences on gene regulation are explored here. An historical perspective is presented to underscore the importance of TE influences on gene regulation with respect to both the discovery of TEs and the early conceptualization of their potential impact on host genome evolution. Evidence that points to a role for TEs in host gene regulation is reviewed, and comparisons between genome sequences are used to demonstrate the fact that TEs are particularly lineage-specific components of their host genomes. Consistent with these two properties of TEs, regulatory effects and evolutionary specificity, human-mouse genome wide sequence comparisons reveal that the regulatory sequences that are contributed by TEs are exceptionally lineage specific. This suggests a particular mechanism by which TEs may drive the diversification of gene regulation between evolutionary lineages.

Animals↗
PubMed2001

PROSPECT improves cis-acting regulatory element prediction by integrating expression profile data with consensus pattern searches.

Consensus pattern and matrix-based searches designed to predict cis-acting transcriptional regulatory sequences have historically been subject to large numbers of false positives. We sought to decrease false positives by incorporating expression profile data into a consensus pattern-based search method. We have systematically analyzed the expression phenotypes of over 6000 yeast genes, across 121 expression profile experiments, and correlated them with the distribution of 14 known regulatory elements over sequences upstream of the genes. Our method is based on a metric we term probabilistic element assessment (PEA), which is a ranking of potential sites based on sequence similarity in the upstream regions of genes with similar expression phenotypes. For eight of the 14 known elements that we examined, our method had a much higher selectivity than a naïve consensus pattern search. Based on our analysis, we have developed a web-based tool called PROSPECT, which allows consensus pattern-based searching of gene clusters obtained from microarray data.

5' Untranslated Regions↗
PubMed2001

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.

Databases, Factual↗
PubMed2001

HMGN4, a newly discovered nucleosome-binding protein encoded by an intronless gene.

We describe a newly discovered nuclear protein, HMGN4, that is closely related to the canonical HMGN2 nucleosome-binding protein. The protein is encoded by an intronless gene, which, in humans, is located in the hereditary hemochromatosis [correction of hemachromatosis] region at position 6p21.3. A single approximately 2-kb HMGN4 mRNA was found to be expressed, in variable amounts, in all human tissues tested; however, the HMGN4 transcript was significantly less abundant than that of HMGN2. The HMGN4 protein could be detected in HeLa cells by Western analysis with an antibody elicited against a unique region of the protein. Transfection of HeLa cells with a plasmid expressing HMGN4-GFP indicated that the protein localizes to the nucleus. Our results expand the multiplicity of the HMGN protein family and increase the known cellular repertoire of nucleosome-binding proteins.

Animals↗
PubMed2000

NBP-45, a novel nucleosomal binding protein with a tissue-specific and developmentally regulated expression.

Here we characterize a novel murine nuclear protein, which we named NBP-45, that is related to the ubiquitous nuclear proteins HMG-14/-17, binds specifically to nucleosome core particles, and can function as a transcriptional activator. NBP-45 mRNA is expressed at low levels and in variable amounts in all mouse tissues tested but is especially abundant in RNA extracted from 7-day-old mouse embryos, suggesting that it functions in early embryonic development. NBP-45 is composed of 406 amino acids and is encoded by a single size transcript. The region spanning the N-terminal 85 amino acids contains three segments that are highly homologous to functionally important domains in the HMG-14/-17 protein family: the nuclear localization signal, the nucleosome binding domain, and the chromatin unfolding domain. The protein region spanning the C-terminal 321 amino acids has a 42% content of negatively charged residues. The first 23 amino acids contain a region necessary for nuclear entry of the protein, the region spanning residues 12-40 is the main nucleosomal binding domain of the protein, and the negatively charged, C-terminal domain is necessary for transcription activation. The functional domains of NBP-45 are indicative of a nuclear protein that binds to nucleosomes, thereby creating a chromatin region of high local negative charge. Our studies establish the nucleosomal binding domain as a protein motif that is present in other than just the ubiquitous HMG-14/-17 proteins. We suggest that the nucleosomal binding domain motif is a protein module that facilitates binding to nucleosomes in chromatin.

Amino Acid Sequence↗
PubMed2000

The histone database: a comprehensive WWW resource for histones and histone fold-containing proteins.

The Histone Database (HDB) is an annotated and searchable collection of all full-length sequences and structures of histone and non-histone proteins containing the histone fold motif. These sequences are both eukaryotic and archaeal in origin. Several new histone fold-containing proteins have been identified, including Spt7p, and a few false positives have been removed from the earlier version of HDB. Database contents include compilations of post-translational modifications for each of the core and linker histones, as well as genomic information in the form of map loci for the human histone gene complement, with the genetic loci linked to Online Mendelian Inheritance in Man (OMIM). Conflicts between similar sequence entries from a number of source databases are also documented. Newly added to the HDB are multiple sequence alignments in which predicted functions of histone fold amino acid residues are annotated. The database is freely accessible through the WWW at http://genome.nhgri.nih.gov/histones/

Amino Acid Sequence↗
PubMed1999

Histone Sequence Database: sequences, structures, post-translational modifications and genetic loci.

The Histone Sequence Database is an annotated and searchable collection of all available histone and histone fold sequences and structures. Particular emphasis has been placed on documenting conflicts between similar sequence entries from a number of source databases, conflicts that are not necessarily documented in the source databases themselves. New additions to the database include compilations of post-translational modifications for each of the core and linker histones, as well as genomic information in the form of map loci for the human histone gene complement, with the genetic loci linked to Online Mendelian Inheritance in Man (OMIM). The database is freely accessible through the World Wide Web at either http://genome.nhgri.nih.gov/histones/ or http://www.ncbi.nlm.nih. gov/Baxevani/HISTONES

Animals↗
PubMed1999

Candidate regulatory sequence elements for cell cycle-dependent transcription in Saccharomyces cerevisiae.

Recent developments in genome-wide transcript monitoring have led to a rapid accumulation of data from gene expression studies. Such projects highlight the need for methods to predict the molecular basis of transcriptional coregulation. A microarray project identified the 420 yeast transcripts whose synthesis displays cell cycle-dependent periodicity. We present here a statistical technique we developed to identify the sequence elements that may be responsible for this cell cycle regulation. Because most gene regulatory sites contain a short string of highly conserved nucleotides, any such strings that are involved in gene regulation will occur frequently in the upstream regions of the genes that they regulate, and rarely in the upstream regions of other genes. Our strategy therefore utilizes statistical procedures to identify short oligomers, five or six nucleotides in length, that are over-represented in upstream regions of genes whose expression peaks at the same phase of the cell cycle. We report, with a high level of confidence, that 9 hexamers and 12 pentamers are over-represented in the upstream regions of genes whose expression peaks at the early G(1), late G(1), S, G(2), or M phase of the cell cycle. Some of these sequence elements show a preference for a particular orientation, and others, through a separate statistical test, for a particular position upstream of the ATG start codon. The finding that the majority of the statistically significant sequence elements are located in late G(1) upstream regions correlates with other experiments that identified the late G(1)/early S boundary as a vital cell cycle control point. Our results highlight the importance of MCB, an element implicated previously in late G(1)/early S gene regulation, as most of the late G(1) oligomers contain the MCB sequence or variations thereof. It is striking that most MCB-like sequences localize to a specific region upstream of the ATG start codon. Additional sequences that we have identified may be important for regulation at other phases of the cell cycle.

5' Untranslated Regions↗
PubMed1999

Threading analysis of prospero-type homeodomains.

The homeodomain is a common structural motif found in many transcription factors involved in cell fate determination during development. We have used threading analysis techniques to predict whether the atypical homeodomain of prospero (pros) family members could form the three-helical homeodomain structural motif, even though these proteins are not statistically similar to canonical homeodomains as assessed by BLAST searches. Amino acid sequences of these divergent homeodomain proteins were threaded through the X-ray coordinates of the Drosophila engrailed homeodomain protein [23]. The analysis confirms that the prospero class of homeodomain proteins is indeed capable of forming the homeodomain structure despite its low degree of sequence identity to the canonical homeodomain. Energy calculations indicate that the homeodomain structure is stabilized primarily by hydrophobic interactions between residues at the helical interfaces. Although the atypical prospero-type homeodomain shows very little sequence similarity when compared to other homeodomain proteins, the critical amino acids responsible for maintaining the three-dimensional structure are highly conserved. A number of other homeodomain proteins, such as PHO2p from Saccharomyces and Pax6 from human, were also included in the threading analysis and were shown to be able to form the engrailed structure, indicating that there are no rigid overall sequence requirements for the formation of the homeodomain structural motif. Based on the threading experiments and the subsequent structural alignment, a new amino acid signature that unambiguously identifies the prospero-type proteins was deduced.

Amino Acid Motifs↗
PubMed1998

AT-hook motifs identified in a wide variety of DNA-binding proteins.

The AT-hook is a small DNA-binding protein motif which was first described in the high mobility group non-histone chromosomal protein HMG-I(Y). Since its discovery, this motif has been observed in other DNA-binding proteins from a wide range of organisms. Using pattern searches and position-dependent matrices, we have extracted the AT-hook motifs present in a non-redundant protein sequence database. We have classified these motifs into three types according to their sequence similarity and have found that they are prevalent in many eukaryotic nuclear proteins in single or multiple copies. Furthermore, AT-hook motifs are frequently associated with known functional domains seen in chromatin proteins and in DNA-binding proteins (e.g. histone folds, homeodomains and zinc fingers). In general, it appears that the AT-hook motif is an auxiliary protein motif cooperating with other DNA-binding activities and facilitating changes in the structure of the DNA either as a polypeptide on its own [e.g. HMG-I(Y)] or as part of a multidomain protein [e.g. Swi2p in Saccharomyces cerevisiae or HRX (ALL-1) in Homo sapiens]. It is most interesting that this motif seems to be quite specific to known or predicted chromosomal/DNA-binding proteins, suggesting that it may act as a versatile minor groove tether.

Amino Acid Sequence↗
PubMed1998

The biochemical and phenotypic characterization of Hho1p, the putative linker histone H1 of Saccharomyces cerevisiae.

There is currently no published report on the isolation and definitive identification of histone H1 in Saccharomyces cerevisiae. It was, however, recently shown that the yeast HHO1 gene codes for a predicted protein homologous to H1 of higher eukaryotes (Landsman, D. (1996) Trends Biochem. Sci. 21, 287-288; Ushinsky, S. C., Bussey, H. , Ahmed, A. A., Wang, Y., Friesen, J., Williams, B. A., and Storms, R. K. (1997) Yeast 13, 151-161), although there is no biochemical evidence that shows that Hho1p is, indeed, yeast histone H1. We showed that purified recombinant Hho1p (rHho1p) has electrophoretic and chromatographic properties similar to linker histones. The protein forms a stable ternary complex with a reconstituted core di-nucleosome in vitro at molar rHho1p:core ratios up to 1. Reconstitution of rHho1p with H1-stripped chromatin confers a kinetic pause at approximately 168 base pairs in the micrococcal nuclease digestion pattern of the chromatin. These results strongly suggest that Hho1p is a bona fide linker histone. We deleted the HHO1 gene and showed that the strain is viable and has no growth or mating defects. Hho1p is not required for telomeric silencing, basal transcriptional repression, or efficient sporulation. Unlike core histone mutations, a hho1Delta strain does not exhibit a Sin or Spt phenotype. The absence of Hho1p does not lead to a change in the nucleosome repeat length of bulk chromatin nor to differences in the in vivo micrococcal nuclease cleavage sites in individual genes as detected by primer extension mapping.

Amino Acid Sequence↗
PubMed1998

Histone Sequence Database: new histone fold family members.

Searches of the major public protein databases with core and linker chicken and human histone sequences have resulted in the compilation of an annotated set of histone protein sequences. In addition, new database searches with two distinct motif search algorithms have identified several members of the histone fold family, including human DRAP1 and yeast CSE4. Database resources include information on conflicts between similar sequence entries in different source databases, multiple sequence alignments, links to the Entrez integrated information retrieval system, structures for histone and histone fold proteins, and the ability to visualize structural data through Cn3D. The database currently contains >1000 protein sequences, which are searchable by protein type, accession number, organism name, or any other free text appearing in the definition line of the entry. All sequences and alignments in this database are available through the World Wide Web at http://www.nhgri.nih. gov/DIR/GTB/HISTONES or http://www.ncbi.nlm.nih. gov/Baxevani/HISTONES

Amino Acid Sequence↗
PubMed1998

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.

Cell Cycle↗
PubMed1998

Homology model building of Hho1p supports its role as a yeast histone H1 protein.

Biochemical studies to date have not been able to identify the linker histone H1 protein in the budding yeast Saccharomyces cerevisiae. Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain. To determine whether Hho1p can assume the shape of an H1 protein, homology model building experiments were performed using the structure of chicken histone H5 globular domain as the basis for comparison. A statistically significant match between each of the two globular domains of Hho1p and the chicken histone H5 structure was obtained, and probability values indicate that there is a less than 1 in 100 chance that such a match would be the result of a random event. These findings support the proposal that Hho1p acts as an "H1 dimer" and could be responsible for the decreased linker DNA length observed between nucleosomal core particles.

Amino Acid Sequence↗
PubMed1997

Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily.

Searches of several sequence databases reveal that human HD1, yeast HDA1, yeast RPD3 and other eukaryotic histone deacetylases share nine motifs with archaeal and eubacterial enzymes, including acetoin utilization protein (acuC) and acetylpolyamine amidohydrolase. Histone deacetylase and acetylpolyamine amidohydrolase also share profound functional similarities in that both: (i) recognize an acetylated aminoalkyl group; (ii) catalyze the removal of the acetyl group by cleaving an amide bond; (iii) increase the positive charge of the substrate. Stabilization of nucleosomal DNA-histone interaction brought about by the change in charge has been implicated as the underlying cause for histone deacetylase-mediated transcriptional repression. We speculate that the eukaryotic histone deacetylases originated from a prokaryotic enzyme similar to the acetylpolyamine amidohydrolases that relied on reversible acetylation and deacetylation of the aminoalkyl group of a DNA binding molecule to achieve a gene regulatory effect.

Acetoin↗