New Nomenclature for Chromatin-Modifying Enzymes

Allis, C. David; Berger, Shelley L.; Côté, Jacques; Dent, Sharon Y.R.; Jenuwien, Thomas; Kouzarides, Tony; Pillus, Lorraine; Reinberg, Danny; Shi, Yang; Shiekhattar, Ramin; Shilatifard, Ali; Workman, Jerry L.; Zhang, Yi

doi:10.1016/j.cell.2007.10.039

Cited by 853 publications

(752 citation statements)

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“…Importantly, one of the deletion mutants showed a dramatically decreased ability to induce the ors genes after coincubation with the streptomycete. This mutant lacks the gcnE gene (16) that encodes a HAT orthologous to the Saccharomyces cerevisiae GCN5 (17,18), also named KAT2 (19) (Table S1). GCN5 and its orthologs are members of several multisubunit coactivator complexes, such as SAGA, ADA, and NuA4, involved in histone acetylation and chromatin restructuring [reviewed in Baker and Grant (20)].…”

Section: Resultsmentioning

confidence: 99%

Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation

Nützmann

Reyes-Domínguez

Scherlach

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

313

270

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Sequence analyses of fungal genomes have revealed that the potential of fungi to produce secondary metabolites is greatly underestimated. In fact, most gene clusters coding for the biosynthesis of antibiotics, toxins, or pigments are silent under standard laboratory conditions. Hence, it is one of the major challenges in microbiology to uncover the mechanisms required for pathway activation. Recently, we discovered that intimate physical interaction of the important model fungus Aspergillus nidulans with the soil-dwelling bacterium Streptomyces rapamycinicus specifically activated silent fungal secondary metabolism genes, resulting in the production of the archetypal polyketide orsellinic acid and its derivatives. Here, we report that the streptomycete triggers modification of fungal histones. Deletion analysis of 36 of 40 acetyltransferases, including histone acetyltransferases (HATs) of A. nidulans, demonstrated that the Saga/Ada complex containing the HAT GcnE and the AdaB protein is required for induction of the orsellinic acid gene cluster by the bacterium. We also showed that Saga/Ada plays a major role for specific induction of other biosynthesis gene clusters, such as sterigmatocystin, terrequinone, and penicillin. Chromatin immunoprecipitation showed that the Saga/Ada-dependent increase of histone 3 acetylation at lysine 9 and 14 occurs during interaction of fungus and bacterium. Furthermore, the production of secondary metabolites in A. nidulans is accompanied by a global increase in H3K14 acetylation. Increased H3K9 acetylation, however, was only found within gene clusters. This report provides previously undescribed evidence of Saga/Ada dependent histone acetylation triggered by prokaryotes.

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Section: Resultsmentioning

confidence: 99%

Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation

Nützmann

Reyes-Domínguez

Scherlach

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

313

270

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“…To explore whether those H3K4 HMTs are recruited by p52 on the MMP9 promoter, we investigated MLL1 and MLL2 (also named KMT2A and KMT2B, respectively; Allis et al, 2007) recruitments to this p52-regulated target gene by ChIP assays. Although we did not detect their recruitment on the IkBa promoter, both MLL1 and MLL2 proteins were tethered on the MMP9 promoter in p52 overexpressing NIH3T3 cells (Figure 6g).…”

Section: Rhd Nls Grr Ankyrin P65mentioning

confidence: 99%

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

et al. 2009

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Constitutive nuclear factor (NF)-jB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-jB inhibitory molecules such as IjBa or p100. Hut-78, a truncated form of p100, constitutively generates p52 and contributes to the development of T-cell lymphomas but the molecular mechanism underlying this oncogenic potential remains unclear. We show here that MMP9 gene expression is induced through the alternative NF-jB-activating pathway in fibroblasts and also on Hut-78 or p52 overexpression in fibroblasts as well as in lymphoma cells. p52 is critical for Hut-78-mediated MMP9 gene induction as a Hut-78 mutant as well as other truncated NF-jB2 proteins that are not processed into p52 failed to induce the expression of this metalloproteinase. Conversely, MMP9 gene expression is impaired in p52-depleted HUT-78 cells. Interestingly, MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IjBa promoter, and the H3K4 trimethyltransferase activity recruited on the MMP9 promoter is impaired in p52-depleted HUT-78 cells. Moreover, MLL1 and MLL2 are associated with Hut-78 in a native chromatin-enriched extract. Thus, we identified a molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-jB-dependent gene induces its expression and potentially the invasive potential of lymphoma cells harbouring constitutive activity of the alternative NF-jB-activating pathway.

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“…Histone acetyltransferase (HAT) catalyzes the acetylation of core histones through the addition of an acetyl group from the pseudo-substrate acetyl coenzyme A (acetylCoA) to the lysine residue on the ε-amino group on the Nterminal of histones. Apart from histone, HATs also have many non-histone protein substrates, suggesting a new nomenclature, KAT for lysine (K) acetyl transferase, replacing the term HAT [3]. However, in the following sections, we will use HAT to avoid possible confusion.…”

Section: Introductionmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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New Nomenclature for Chromatin-Modifying Enzymes

Cited by 853 publications

References 0 publications

Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation

Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

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