Characterization of two putative histone deacetylase genes from Aspergillus nidulans

Graessle, Stefan; Dangl, Markus; Haas, Hubertus; Mair, Karin; Trojer, Patrick; Brandtner, Eva-Maria; Walton, Jonathan D.; Loidl, Peter; Brosch, Gerald

doi:10.1016/s0167-4781(00)00093-2

Cited by 49 publications

(62 citation statements)

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“…Like other organisms, filamentous fungi have multiple HDACs (7,11,22,23,40). Potential mechanisms of toxin resistance that could be detected by fractionation of the HDACs of C. carbonum could be a novel HDAC activity, reduced levels of sensitive HDAC activity, higher levels of resistant HDAC activity, or conversion of a normally sensitive HDAC to resistance by posttranslational modification.…”

Section: Resultsmentioning

confidence: 99%

“…As a further investigation into the possibility that resistance is the result of qualitative differences among the HDACs of toxin-resistant and toxin-sensitive isolates, we examined the structure and expression of the C. carbonum HDAC genes. N. crassa, A. nidulans, and C. carbonum have HDACs related to yeast RPD3, HDA1, HOS2, and HOS3, but apparently do not have a homolog of yeast HOS1 (7,22,23). This is based on several attempts to find such a gene by using PCR primers based on HOS1, and on BLAST searching with all of the known fungal HDAC genes against the completed genomes of N. crassa (http://www-genome.wi.mit.edu), A. nidulans (http://microbial-.cereon.com), C. heterostrophus (http://www.nadii.com), and the basidiomycete Phanerochaete chrysosporium (http://www.jgi.doe.gov/programs/whiterot.htm).…”

Section: Resultsmentioning

confidence: 99%

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Characterization of Inhibitor-Resistant Histone Deacetylase Activity in Plant-Pathogenic Fungi

et al. 2002

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HC-toxin, a cyclic peptide made by the filamentous fungus Cochliobolus carbonum, is an inhibitor of histone deacetylase (HDAC) from many organisms. It was shown earlier that the HDAC activity in crude extracts of C. carbonum is relatively insensitive to HC-toxin as well as to the chemically unrelated HDAC inhibitors trichostatin and D85, whereas the HDAC activity of Aspergillus nidulans is sensitive (G. Brosch et al., Biochemistry 40:12855-12863, 2001). Here we report that HC-toxin-resistant HDAC activity was present in other, but not all, plant-pathogenic Cochliobolus species but not in any of the saprophytic species tested. The HDAC activities of the fungi Alternaria brassicicola and Diheterospora chlamydosporia, which also make HDAC inhibitors, were resistant. The HDAC activities of all C. carbonum isolates tested, except one non-toxin-producing isolate, were resistant. In a cross between a sensitive isolate and a resistant isolate, resistance genetically cosegregated with HC-toxin production. When fractionated by anion-exchange chromatography, extracts of resistant and sensitive isolates and species had two peaks of HDAC activity, one that was fully HC-toxin resistant and a second that was larger and sensitive. The first peak was consistently smaller in extracts of sensitive fungi than in resistant fungi, but the difference appeared to be insufficiently large to explain the differential sensitivities of the crude extracts. Differences in mRNA expression levels of the four known HDAC genes of C. carbonum did not account for the observed differences in HDAC activity profiles. When mixed together, resistant extracts protected extracts of sensitive C. carbonum but did not protect other sensitive Cochlibolus species or Neurospora crassa. Production of this extrinsic protection factor was dependent on TOXE, the transcription factor that regulates the HC-toxin biosynthetic genes. The results suggest that C. carbonum has multiple mechanisms of self-protection against HC-toxin.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Characterization of Inhibitor-Resistant Histone Deacetylase Activity in Plant-Pathogenic Fungi

et al. 2002

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“…While the S. cerevisiae HDACs Hda1, Rpd3 (a homolgue of the A. nidulans HDAC RpdA [20]), and Sir2 (a homologue of HstA) are each involved in the suppression of a unique set of genes, they also contribute to the silencing of numerous shared genes (1). Likewise, the Schizosaccharomyces pombe HDACs Clr3, Clr6, Sir2, and Hos2 (homologous to A. nidulans HdaA, RpdA, HstA, and HosA [20], respectively) repress both unique and shared genes (22,41). The genes repressed by Clr3 and Sir2 demonstrate particularly strong overlap and also tend to overlap with genes regulated by the heterochromatin-associated protein Swi6 (41).…”

Section: Discussionmentioning

confidence: 99%

“…Hypoacetylation of chromatin is also predominant in subtelomeric chromosomal regions (24). In the model fungus A. nidulans, the HDACs have been studied in particular detail (20,38,39). Therefore, this group of enzymes was chosen to study the effects of histone deacetylation on small-molecule production.…”

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Histone Deacetylase Activity Regulates Chemical Diversity in Aspergillus

et al. 2007

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Bioactive small molecules are critical in Aspergillus species during their development and interaction with other organisms. Genes dedicated to their production are encoded in clusters that can be located throughout the genome. We show that deletion of hdaA, encoding an Aspergillus nidulans histone deacetylase (HDAC), causes transcriptional activation of two telomere-proximal gene clusters-and subsequent increased levels of the corresponding molecules (toxin and antibiotic)-but not of a telomere-distal cluster. Introduction of two additional HDAC mutant alleles in a ⌬hdaA background had minimal effects on expression of the two HdaA-regulated clusters. Treatment of other fungal genera with HDAC inhibitors resulted in overproduction of several metabolites, suggesting a conserved mechanism of HDAC repression of some secondary-metabolite gene clusters. Chromatin regulation of small-molecule gene clusters may enable filamentous fungi to successfully exploit environmental resources by modifying chemical diversity.A distinguishing characteristic of filamentous fungi is their ability to produce a wide variety of small molecules that aid in their survival and pathogenicity. These include compounds, such as pigments, that play a role in virulence and protect the fungus from environmental damage, as well as toxins that kill host tissues or hinder competition from other organisms. These secondary metabolites (SM) (27) can also impact humans in both beneficial and detrimental ways. Many widely used pharmaceuticals are natural products of fungi, as are some of the most potent carcinogens yet identified. Genetic studies, augmented by analysis of whole genome sequences, have revealed that most fungal SM biosynthetic genes are found in compact clusters functioning as individual genetic loci (27). The genus Aspergillus, whose members include toxinproducing pathogens (Aspergillus flavus and A. fumigatus) and pharmaceutical-producing species (A. nidulans and A. terreus), is renowned for prodigious metabolite production and serves as the model for natural-product exploration. Detailed comparison of the genomes of several aspergilli indicates a genomic landscape in which the greatest diversity between species is represented in these SM clusters (28).There has been considerable debate as to the role that gene clustering plays in the secondary metabolism of fungi. Such gene arrangement must be advantageous to the fungus; if natural selection did not favor clustering, one would assume that processes such as gene translocation and unequal crossing over would have caused dispersal over evolutionary history. Support for horizontal transfer from prokaryotes, in which genes are often arranged into operons, exists for the penicillin biosynthetic cluster (9) but not for other fungal clusters. A prokaryotic gene transfer hypothesis is weakened by the fact that fungal SM genes often contain introns and employ codon usage typical of other fungal genes. Another hypothesis holds that clustering provides a selective advantage to the cluster itself i...

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“…Protoplasts growing under selective conditions were further screened for hdaA deletion by a PCR approach. In order to obtain transformants with a homologous integration of the deletion fragment, colonies from homokaryotic spores were picked, and (single) genomic integration was confirmed by Southern blot analysis as described earlier (19).…”

Section: Methodsmentioning

confidence: 99%

HdaA, a Major Class 2 Histone Deacetylase of Aspergillus nidulans , Affects Growth under Conditions of Oxidative Stress

et al. 2005

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Histone deacetylases (HDACs) catalyze the removal of acetyl groups from the -amino group of distinct lysine residues in the amino-terminal tail of core histones. Since the acetylation status of core histones plays a crucial role in fundamental processes in eukaryotic organisms, such as replication and regulation of transcription, recent research has focused on the enzymes responsible for the acetylation/deacetylation of core histones. Very recently, we showed that HdaA, a member of the Saccharomyces cerevisiae HDA1-type histone deacetylases, is a substantial contributor to total HDAC activity in the filamentous fungus Aspergillus nidulans. Now we demonstrate that deletion of the hdaA gene indeed results in the loss of the main activity peak and in a dramatic reduction of total HDAC activity. In contrast to its orthologs in yeast and higher eukaryotes, HdaA has strong intrinsic activity as a protein monomer when expressed as a recombinant protein in a prokaryotic expression system. In vivo, HdaA is involved in the regulation of enzymes which are of vital importance for the cellular antioxidant response in A. nidulans. Consequently, ⌬hdaA strains exhibit significantly reduced growth on substrates whose catabolism generates molecules responsible for oxidative stress conditions in the fungus. Our analysis revealed that reduced expression of the fungal catalase CatB is jointly responsible for the significant growth reduction of the hdaA mutant strains.In eukaryotic organisms, DNA and highly basic nuclear proteins, the histones, constitute the nucleosome, which is the essential structural subunit of the chromatin. The fact that the N-terminal extensions of the core histones contain distinct sites for various posttranslational modifications alters our view of chromatin as being a static entity for the efficient packing of the genomic DNA into the nucleus of the cell. Today it is accepted that, in addition to its structural role, chromatin has an important regulatory function during DNA replication and repair, cell cycle control, cell aging, and transcription (for a review, see reference 59).Antagonistic enzymes such as kinases/phosphatases (10, 39), histone methyltransferases/demethylases (for a review, see reference 9), and histone acetyltransferases/deacetylases (for a review, see reference 38) are responsible for a dynamic equilibrium of chromatin regulating modifications of the histone tails.The acetylation of distinct lysine residues of H2A, H2B, H3, and H4 is the most prominent dynamic histone modification allowing or denying the access of numerous regulatory proteins, such as transcription factors, to distinct regions of genomic DNA. Although histone acetylation is by far the beststudied type of histone modification, our understanding of how this modification is linked to processes such as the regulation of transcription is still very limited. However, acetylated histones are a characteristic feature of transcriptionally active chromatin (2), and hypoacetylated histones accumulate within transcriptionally silenc...

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Characterization of two putative histone deacetylase genes from Aspergillus nidulans

Cited by 49 publications

References 50 publications

Characterization of Inhibitor-Resistant Histone Deacetylase Activity in Plant-Pathogenic Fungi

Characterization of Inhibitor-Resistant Histone Deacetylase Activity in Plant-Pathogenic Fungi

Histone Deacetylase Activity Regulates Chemical Diversity in Aspergillus

HdaA, a Major Class 2 Histone Deacetylase of Aspergillus nidulans , Affects Growth under Conditions of Oxidative Stress

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