Biomedical subjects

Lars Hennig

Publications and source records attributed to Lars Hennig.

At least 19 recordsLinked to original sources

PubMed2006

Chromatin assembly factor CAF-1 is required for cellular differentiation during plant development.

Chromatin assembly factor CAF-1 facilitates the formation of nucleosomes on newly replicated DNA in vitro. However, the role of CAF-1 in development is poorly understood because mutants are not available in most multicellular model organisms. Biochemical evidence suggests that FASCIATA1, FASCIATA2 and MSI1 form CAF-1 in Arabidopsis thaliana. Because fasciata mutants are viable, CAF-1 is not essential for cell division in plants. Arabidopsis CAF-1 mutants have defects in shoot apical meristems; in addition, CAF-1 is required to establish seedling architecture, leaf size and trichome differentiation. CAF-1 is needed to restrict branching of trichomes on rosette leaves. Increased trichome branching in CAF-1 mutants is not strictly correlated with increased nuclear DNA content. In addition, fas2 glabra3 double mutants show an additive genetic interaction, demonstrating that CAF-1 acts genetically parallel to the GLABRA3-containing, endoreduplication-coupled trichome branching pathway. However, CAF-1 is often needed to restrict endoreduplication, because seedlings of most CAF-1 mutants have increased ploidy. Notably, in the Landsberg erecta background, loss of CAF-1 does not affect ploidy, demonstrating that loss of CAF-1 can be compensated in some Arabidopsis accessions. These results reveal that the functions of FAS1, FAS2 and MSI1 are not restricted to meristems, but are also needed to control genome replication at multiple steps of development.

Animals↗

PubMed2006

Polycomb-group proteins repress the floral activator AGL19 in the FLC-independent vernalization pathway.

Polycomb-group (PcG) proteins form a cellular memory by maintaining developmental regulators in a transcriptionally repressed state. We identified a novel flowering gene that is under PcG control in Arabidopsis--the MADS-box gene AGL19. AGL19 expression is maintained at very low levels by the PcG proteins MSI1, CLF, and EMF2, and AGL19 is partly responsible for the early flowering phenotype of clf mutants. AGL19 chromatin is strongly enriched in trimethylation of Lys 27 on histone H3 (H3K27me3) but not in H3K9me2. Repressive H3K27me3 marks were reduced by decreased CLF or MSI1 levels and by prolonged cold, suggesting that the PcG proteins MSI1 and CLF repress AGL19 in the absence of cold. Ectopic expression of AGL19 strongly accelerates flowering, and agl19 mutants have a decreased response to vernalization, the promotion of flowering by prolonged cold. Epistasis analyses revealed that AGL19 works in the poorly characterized FLC-independent vernalization pathway and does not require SOC1 to function. In this pathway, prolonged cold relieves AGL19 from PcG repression by a mechanism that requires VIN3 but not VRN2. Elevated AGL19 levels activate LFY and AP1 and eventually cause flowering.

Arabidopsis↗

PubMed2006

Regulation of flowering time by Arabidopsis MSI1.

The transition to flowering is tightly controlled by endogenous programs and environmental signals. We found that MSI1 is a novel flowering-time gene in Arabidopsis. Both partially complemented msi1 mutants and MSI1 antisense plants were late flowering, whereas ectopic expression of MSI1 accelerated flowering. Physiological experiments revealed that MSI1 is similar to genes from the autonomous promotion of flowering pathway. Expression of most known flowering-time genes did not depend on MSI1, but the induction of SOC1 was delayed in partially complemented msi1 mutants. Delayed activation of SOC1 is often caused by increased expression of the floral repressor FLC. However, MSI1 function is independent of FLC. MSI1 is needed to establish epigenetic H3K4 di-methylation and H3K9 acetylation marks in SOC1 chromatin. The presence of these modifications correlates with the high levels of SOC1 expression that induce flowering in Arabidopsis. Together, the control of flowering time depends on epigenetic mechanisms for the correct expression of not only the floral repressor FLC, but also the floral activator SOC1.

Arabidopsis↗

PubMed2006

Optimized heart failure therapy and complete anemia correction on left-ventricular hypertrophy in nondiabetic and diabetic patients undergoing hemodialysis.

BACKGROUND: According to new guidelines, diabetes mellitus per se can be considered as stage I chronic heart failure (CHF). Available evidence suggests that patients suffering from both diabetes mellitus and renal insufficiency have disproportionately high rates of left-ventricular hypertrophy (LVH). METHODS: Optimized heart failure therapy, including beta-blockers, ACE-inhibitors and AT II-type-1-receptor-blockers, was prescribed in combination with complete anemia correction using epoetin beta (target hemoglobin: 13.5 g/dl for women; 14.5 g/dl for men) to 230 patients (55% male) with ambulatory hemodialysis, including 60 patients (52% male) with diabetes. Echocardiographic follow-up examinations were performed over a mean period of 4.4 +/- 1.2 years. RESULTS: Mean hemoglobin levels at the study end significantly increased to target levels in the entire study population and in patients with diabetes (both p < 0.001). Compared with baseline, significant improvements were seen in hemodialysis patients - both without and with diabetes - in left-ventricular mass index (-28.8 g/m2 [p < 0.001] and 29.0 g/m2 [p < 0.005], respectively), left-ventricular ejection fraction (+7.0% [p < 0.001] and +8.3% [p < 0.01], respectively) and in NYHA class (-0.84 [p < 0.01] and -1.12 [p < 0.01], respectively). Similar to the results in the overall population, a highly significant reduction in LVH (p < 0.005) and significant improvements in LVEF (p < 0.01) and NYHA class (p < 0.01) were seen in the high-risk subgroup of diabetic patients. CONCLUSIONS: Patients undergoing hemodialysis, with or without concomitant diabetes, benefit considerably from optimized, multifactorial heart failure therapy combined with complete anemia correction.

Acid-Base Equilibrium↗

PubMed2006

A systematic comparison and evaluation of biclustering methods for gene expression data.

MOTIVATION: In recent years, there have been various efforts to overcome the limitations of standard clustering approaches for the analysis of gene expression data by grouping genes and samples simultaneously. The underlying concept, which is often referred to as biclustering, allows to identify sets of genes sharing compatible expression patterns across subsets of samples, and its usefulness has been demonstrated for different organisms and datasets. Several biclustering methods have been proposed in the literature; however, it is not clear how the different techniques compare with each other with respect to the biological relevance of the clusters as well as with other characteristics such as robustness and sensitivity to noise. Accordingly, no guidelines concerning the choice of the biclustering method are currently available. RESULTS: First, this paper provides a methodology for comparing and validating biclustering methods that includes a simple binary reference model. Although this model captures the essential features of most biclustering approaches, it is still simple enough to exactly determine all optimal groupings; to this end, we propose a fast divide-and-conquer algorithm (Bimax). Second, we evaluate the performance of five salient biclustering algorithms together with the reference model and a hierarchical clustering method on various synthetic and real datasets for Saccharomyces cerevisiae and Arabidopsis thaliana. The comparison reveals that (1) biclustering in general has advantages over a conventional hierarchical clustering approach, (2) there are considerable performance differences between the tested methods and (3) already the simple reference model delivers relevant patterns within all considered settings.

Algorithms↗

PubMed2006

Functional genomic analysis of CAF-1 mutants in Arabidopsis thaliana.

Duplication of chromatin following DNA replication requires spatial reorganization of chromatin domains assisted by chromatin assembly factor CAF-1. Here, we tested the genomic consequences of CAF-1 loss and the function of chromatin assembly factor CAF-1 in heterochromatin formation. Genes located in heterochromatic regions are usually silent, and we found that this transcriptional repression persists in the absence of CAF-1 in Arabidopsis. However, using microarrays we observed that genes that are active during late S-phase, when heterochromatin is duplicated, were up-regulated in CAF-1 mutants. Arabidopsis CAF-1 mutants also have reduced cytological heterochromatin content; however, DNA methylation of pericentromeric repeats was normal, demonstrating that CAF-1 is not required for maintenance of DNA methylation. Instead, hypomethylation of the genome, which has only mild effects on the development of wild-type plants, completely arrested development of CAF-1 mutants. These results suggest that CAF-1 functions in heterochromatin formation. CAF-1 and DNA methylation, which is also needed for heterochromatin formation, have partially redundant functions that are essential for cell proliferation. Interestingly, transcriptional repression and heterochromatin compaction can be genetically separated, and CAF-1 is required only for the complete compaction of heterochromatin but not to maintain transcriptional repression of heterochromatic genes.

Arabidopsis↗

PubMed2006

MIAME/Plant - adding value to plant microarrray experiments.

Appropriate biological interpretation of microarray data calls for relevant experimental annotation. The widely accepted MIAME guidelines provide a generic, organism-independant standard for minimal information about microarray experiments. In its overall structure, MIAME is very general and specifications cover mostly technical aspects, while relevant organism-specific information useful to understand the underlying experiments is largely missing. If plant biologists want to use results from published microarray experiments, they need detailed information about biological aspects, such as growth conditions, harvesting time or harvested organ(s). Here, we propose MIAME/Plant, a standard describing which biological details to be captured for describing microarray experiments involving plants. We expect that a more detailed and more systematic annotation of microarray experiments will greatly increase the use of transcriptome data sets for the scientific community. The power and value of systematic annotation of microarray data is convincingly demonstrated by data warehouses such as Genevestigator(R) or NASCArrays, and better experimental annotation will make these applications even more powerful.

Editorial↗

PubMed2005

Genome-wide identification of potential plant E2F target genes.

Entry into the S phase of the cell cycle is controlled by E2F transcription factors that induce the transcription of genes required for cell cycle progression and DNA replication. Although the E2F pathway is highly conserved in higher eukaryotes, only a few E2F target genes have been experimentally validated in plants. We have combined microarray analysis and bioinformatics tools to identify plant E2F-responsive genes. Promoter regions of genes that were induced at the transcriptional level in Arabidopsis (Arabidopsis thaliana) seedlings ectopically expressing genes for the E2Fa and DPa transcription factors were searched for the presence of E2F-binding sites, resulting in the identification of 181 putative E2F target genes. In most cases, the E2F-binding element was located close to the transcription start site, but occasionally could also be localized in the 5' untranslated region. Comparison of our results with available microarray data sets from synchronized cell suspensions revealed that the E2F target genes were expressed almost exclusively during G1 and S phases and activated upon reentry of quiescent cells into the cell cycle. To test the robustness of the data for the Arabidopsis E2F target genes, we also searched for the presence of E2F-cis-acting elements in the promoters of the putative orthologous rice (Oryza sativa) genes. Using this approach, we identified 70 potential conserved plant E2F target genes. These genes encode proteins involved in cell cycle regulation, DNA replication, and chromatin dynamics. In addition, we identified several genes for potentially novel S phase regulatory proteins.

Arabidopsis↗

PubMed2005

Effects of optimized heart failure therapy and anemia correction with epoetin beta on left ventricular mass in hemodialysis patients.

BACKGROUND: In chronic hemodialysis (HD) patients, the presence and degree of left ventricular hypertrophy (LVH) correlates with mortality. Previous studies have shown that interventions, such as anemia correction or treatment of hypertension and/or chronic heart failure (CHF), can result in moderate regression of LVH. The primary objective of our study was to investigate the effects of a multi-interventional treatment strategy on LVH in HD patients. METHODS AND RESULTS: In a series of 202 consecutive HD patients, we combined optimized CHF therapy, including beta-blockers (BB), ACE inhibitors and angiotensin receptor blockers (ARBs), to target doses with full anemia correction by epoetin beta (hemoglobin (Hb) target males 14.5 g/dl, females 13.5 g/dl). Serial echocardiograms were recorded every 3-6 months. Mean follow-up was 3.4 +/- 1.2 years. Mean Hb at baseline was 11.4 +/- 1.4 vs. 14.6 +/- 1.6 g/dl (p < 0.001) at study end. There was a significant reduction in left ventricular mass index (LVMI, 159 +/- 65 vs. 132 +/- 46 g/m2 (p < 0.001)), an improvement in left ventricular ejection fraction (LVEF, 60 +/- 15 vs. 66 +/- 12% (p < 0.01)) and in NYHA class (2.8 +/- 0.76 vs. 1.96 +/- 0.76 (p < 0.01)) from baseline to follow-up in the overall study population. In a subgroup of 70 patients, LVMI returned to normal (169 +/- 33 vs. 114 +/- 14 g/m2 (p < 0.001)) after 1.4 +/- 1 years. CONCLUSIONS: Our study shows that optimized CHF therapy, in combination with anemia correction to normal Hb targets, results in a significant reduction of LVH, an increase in LVEF and an improvement in NYHA class. Moreover, in contrast to previous studies, our data also demonstrate that complete regression and prevention of LVH in HD patients is possible.

Adrenergic beta-Antagonists↗

PubMed2005

MSI1-like proteins: an escort service for chromatin assembly and remodeling complexes.

MSI1-like WD40 repeat proteins are subunits of many protein complexes controlling chromatin dynamics. These proteins do not have any catalytic activity, but several recent studies using loss-of-function mutants established specific functions during development. Here, we review the current knowledge of MSI1-like proteins, including their phylogenetic history, expression patterns, biochemical interactions and mutant phenotypes. MSI1-like proteins, which are often targets or partners of tumor-suppressor proteins, are required during cell proliferation and differentiation in flies, nematodes and plants. We discuss the possibility that MSI1-like proteins could function to maintain epigenetic memory during development by targeting silencing complexes to chromatin during nucleosome assembly.

Animals↗

PubMed2005

Gene-expression analysis and network discovery using Genevestigator.

The Genevestigator software suite belongs to a new generation of web-based tools that provide categorized quantitative information about elements (genes or annotations) contained in large microarray databases. The first version of Genevestigator, in use since 2004, has now been updated to enable faster, more powerful and more diverse types of queries for gene-function analysis and network discovery.

Databases, Genetic↗

PubMed2004

Sparse graphical Gaussian modeling of the isoprenoid gene network in Arabidopsis thaliana.

We present a novel graphical Gaussian modeling approach for reverse engineering of genetic regulatory networks with many genes and few observations. When applying our approach to infer a gene network for isoprenoid biosynthesis in Arabidopsis thaliana, we detect modules of closely connected genes and candidate genes for possible cross-talk between the isoprenoid pathways. Genes of downstream pathways also fit well into the network. We evaluate our approach in a simulation study and using the yeast galactose network.

Arabidopsis↗

PubMed2004

Transcriptional programs of early reproductive stages in Arabidopsis.

The life cycle of flowering plants alternates between a diploid sporophytic and a haploid gametophytic generation. After fertilization of each the egg and central cells by one male gamete, the development of both fertilization products occurs coordinated with the maternally derived seed coat and carpel tissues forming the fruit. The reproduction program is likely to involve the concerted activity of many genes. To identify genes with specific functions during reproduction, we have analyzed the expression profile of more than 22,000 genes present on the Arabidopsis ATH1 microarray during three stages of flower and fruit development. We found 1,886 genes regulated during reproductive development and 1,043 genes that were specifically expressed during reproduction. When compared to cells from an Arabidopsis suspension culture, S-phase genes were underrepresented and G2 and M-phase genes were strongly enriched in the set of specific genes, indicating that important functions during reproduction are exerted in the G2 and M phases of the cell cycle. Many potential signaling components, such as receptor-like protein kinases, phosphatases, and transcription factors, were present in both groups of genes. Members of the YABBY, MADS box, and Myb transcription factor families were significantly overrepresented in the group of specific genes, revealing an important role of these families during reproduction. Furthermore, we found a significant enrichment of predicted secreted proteins smaller than 15 kD that could function directly as signaling molecules or as precursors for peptide hormones. Our study provides a basis for targeted reverse-genetic approaches aimed to identify key genes of reproductive development in plants.

Arabidopsis↗

PubMed2004

GENEVESTIGATOR. Arabidopsis microarray database and analysis toolbox.

High-throughput gene expression analysis has become a frequent and powerful research tool in biology. At present, however, few software applications have been developed for biologists to query large microarray gene expression databases using a Web-browser interface. We present GENEVESTIGATOR, a database and Web-browser data mining interface for Affymetrix GeneChip data. Users can query the database to retrieve the expression patterns of individual genes throughout chosen environmental conditions, growth stages, or organs. Reversely, mining tools allow users to identify genes specifically expressed during selected stresses, growth stages, or in particular organs. Using GENEVESTIGATOR, the gene expression profiles of more than 22,000 Arabidopsis genes can be obtained, including those of 10,600 currently uncharacterized genes. The objective of this software application is to direct gene functional discovery and design of new experiments by providing plant biologists with contextual information on the expression of genes. The database and analysis toolbox is available as a community resource at https://www.genevestigator.ethz.ch.

Arabidopsis↗

PubMed2003

Arabidopsis MSI1 is a component of the MEA/FIE Polycomb group complex and required for seed development.

Seed development in angiosperms initiates after double fertilization, leading to the formation of a diploid embryo and a triploid endosperm. The active repression of precocious initiation of certain aspects of seed development in the absence of fertilization requires the Polycomb group proteins MEDEA (MEA), FERTILIZATION-INDEPENDENT ENDOSPERM (FIE) and FERTILIZATION-INDEPENDENT SEED2. Here we show that the Arabidopsis WD-40 domain protein MSI1 is present together with MEA and FIE in a 600 kDa complex and interacts directly with FIE. Mutant plants heterozygous for msi1 show a seed abortion ratio of 50% with seeds aborting when the mutant allele is maternally inherited, irrespective of a paternal wild-type or mutant MSI1 allele. Further more, msi1 mutant gametophytes initiate endosperm development in the absence of fertilization at a high penetrance. After pollination, only the egg cell becomes fertilized, the central cell starts dividing prior to fertilization, resulting in the formation of seeds containing embryos surrounded by diploid endosperm. Our results establish that MSI1 has an essential function in the correct initiation and progression of seed development.

Arabidopsis↗

PubMed2003

The Polycomb-group protein MEDEA regulates seed development by controlling expression of the MADS-box gene PHERES1.

The Polycomb-group (PcG) proteins MEDEA, FERTILIZATION INDEPENDENT ENDOSPERM, and FERTILIZATION INDEPENDENT SEED2 regulate seed development in Arabidopsis by controlling embryo and endosperm proliferation. All three of these FIS-class proteins are likely subunits of a multiprotein PcG complex, which epigenetically regulates downstream target genes that were previously unknown. Here we show that the MADS-box gene PHERES1 (PHE1) is commonly deregulated in the fis-class mutants. PHE1 belongs to the evolutionarily ancient type I class of MADS-box proteins that have not yet been assigned any function in plants. Both MEDEA and FIE directly associate with the promoter region of PHE1, suggesting that PHE1 expression is epigenetically regulated by PcG proteins. PHE1 is expressed transiently after fertilization in both the embryo and the endosperm; however, it remains up-regulated in the fis mutants, consistent with the proposed function of the FIS genes as transcriptional repressors. Reduced expression levels of PHE1 in medea mutant seeds can suppress medea seed abortion, indicating a key role of PHE1 repression in seed development. PHE1 expression in a hypomethylated medea mutant background resembles the wild-type expression pattern and is associated with rescue of the medea seed-abortion phenotype. In summary, our results demonstrate that seed abortion in the medea mutant is largely mediated by deregulated expression of the type I MADS-box gene PHE1.

Arabidopsis↗

PubMed2003

Genome-wide gene expression in an Arabidopsis cell suspension.

Plant cell suspension cultures are invaluable models for the study of cellular processes. Here we develop the recently described Arabidopsis suspension culture MM2d as a transcript profiling platform by means of Affymetrix ATH1 microarrays. Analysis of gene expression profiles during normal culture growth, during synchronous cell cycle re-entry and during synchronous cell cycle progression provides a unique integrated view of gene expression responses in a higher-plant system. Particularly striking is that expression of over 14 000 genes belonging to all defined categories can be reliably detected, suggesting that integrated and comparative analysis of data sets derived from transcript profiling of cultures is a powerful approach to identify candidate components involved in a wide range of biological processes. Combinatorial analysis of independent cell cycle synchrony methods allows the identification of genes that are apparently cell-cycle-regulated but are most likely responding to the induction of synchrony. We thus present an integrated genome-wide view of the transcriptional profile of a plant suspension culture and identify a refined set of 1082 cell cycle regulated genes largely independent of synchrony method.

Aphidicolin↗

PubMed2003

Arabidopsis transcript profiling on Affymetrix GeneChip arrays.

DNA microarrays are becoming a frequently used research tool. Whilst several studies have confirmed the reproducibility of analysing the same RNA samples on duplicate arrays, there is little analysis of the reproducibility of the results of transcript profiling between microarrays carrying different probes to a common set of genes. To address this question, we compared the performance and reproducibility of two microarrays commonly used in plant research, the Affymetrix Arabidopsis AG array containing more than 8000 probe sets and the Affymetrix Arabidopsis ATH1 array containing more than 22,000 redesigned probe sets. A total of 21 different RNA samples were labelled and hybridized in parallel to the two microarray types. Focusing on the overlap of more than 7300 targets detected with both arrays, we found a high degree of reproducibility. Despite the use of different probe sets, both signal and signal log ratio were very similar for most genes. However, genes that were called absent or not changed by Affymetrix' statistical algorithm implemented in MAS5.0 showed considerably less conservation of expression patterns. Moreover, we identified about 300 genes that yielded strongly different measurements with the two microarrays, emphasizing that RNA profiling data need careful interpretation. Overall, this study shows that results obtained with ATH1 and AG arrays are very comparable and hence that the analysis is largely independent of probe sets. However, the result emphasize the need for appropriate filtering schemes such as those based on the present and change calls provided by MAS5.0 rather than reliance solely on signal values.

Arabidopsis↗