A Gene Cluster That Encodes Histone Deacetylase Inhibitors Contributes to Bacterial Persistence and Antibiotic Tolerance in Burkholderia thailandensis.

Persister cells are genetically identical variants in a bacterial population that have phenotypically modified their physiology to survive environmental stress. In bacterial pathogens, persisters are able to survive antibiotic treatment and reinfect patients in a frustrating cycle of chronic infection. To better define core persistence mechanisms for therapeutics development, we performed transcriptomics analyses of Burkholderia thailandensis populations enriched for persisters via three methods: flow sorting for low proton motive force, meropenem treatment, and culture aging. Although the three persister-enriched populations generally displayed divergent gene expression profiles that reflect the multimechanistic nature of stress adaptations, there were several common gene pathways activated in two or all three populations.
These include polyketide and nonribosomal peptide synthesis, Clp proteases, mobile elements, enzymes involved in lipid metabolism, and ATP-binding cassette (ABC) transporter systems. In particular, identification of genes that encode polyketide synthases (PKSs) and fatty acid catabolism factors indicates that generation of secondary metabolites, natural products, and complex lipids could be part of the metabolic program that governs the persistence state.
We also found that loss-of-function mutations in the PKS-encoding gene locus BTH_I2366, which plays a role in biosynthesis of histone deacetylase (HDAC) inhibitors, resulted in increased sensitivity to antibiotics targeting DNA replication. Furthermore, treatment of multiple bacterial pathogens with a fatty acid synthesis inhibitor, CP-640186, potentiated the efficacy of meropenem against the persister populations. Altogether, our results suggest that bacterial persisters may exhibit an outwardly dormant physiology but maintain active metabolic processes that are required to maintain persistence.
The discovery of antibiotics such as penicillin and streptomycin marked a historic milestone in the 1940s and heralded a new era of antimicrobial therapy as the modern standard for medical treatment. Yet, even in those early days of discovery, it was noted that a small subset of cells (∼1 in 105) survived antibiotic treatment and continued to persist, leading to recurrence of chronic infection. These persisters are phenotypic variants that have modified their physiology to survive environmental stress.
In this study, we have performed three transcriptomic screens to identify persistence genes that are common between three different stressor conditions. In particular, we identified genes that function in the synthesis of secondary metabolites, small molecules, and complex lipids, which are likely required to maintain the persistence state. Targeting universal persistence genes can lead to the development of clinically relevant antipersistence therapeutics for infectious disease management.

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.

Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined.TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred.
We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity.This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies.

The HosA Histone Deacetylase Regulates Aflatoxin Biosynthesis Through Direct Regulation of Aflatoxin Cluster Genes

Histone deacetylases (HDACs) always function as corepressors and sometimes as coactivators in the regulation of fungal development and secondary metabolite production. However, the mechanism through which HDACs play positive roles in secondary metabolite production is still unknown. Here, classical HDAC enzymes were identified and analyzed in Aspergillus flavus, a fungus that produces one of the most carcinogenic secondary metabolites, aflatoxin B1 (AFB1). Characterization of the HDACs revealed that a class I family HDAC, HosA, played crucial roles in growth, reproduction, the oxidative stress response, AFB1 biosynthesis, and pathogenicity. To a lesser extent, a class II family HDAC, HdaA, was also involved in sclerotia formation and AFB1 biosynthesis. An in vitro analysis of HosA revealed that its HDAC activity was considerably diminished at nanomolar concentrations of trichostatin A. Notably, chromatin immunoprecipitation experiments indicated that HosA bound directly to AFB1 biosynthesis cluster genes to regulate their expression. Finally, we found that a transcriptional regulator, SinA, interacts with HosA to regulate fungal development and AFB1 biosynthesis. Overall, our results reveal a novel mechanism by which classical HDACs mediate the induction of secondary metabolite genes in fungi.

A novel ECL method for histone acetyltransferases (HATs) activity analysis by integrating HCR signal amplification and ECL silver clusters.

A novel electrogenerated chemiluminescence (ECL) method combining ECL property of silver clusters and hybridization chain reaction (HCR) signal amplification strategy has been designed for the analysis of histone acetyltransferases (HATs) activity and inhibitor evaluation. In this strategy, the substrate peptide of HAT released from the electrode surface due to the charge change based on the acetylated reaction in the presence of HATs, and then the exposed DNA on the electrode initiated the HCR to form the supersandwich DNA sequence, which can adsorb Ag+, and the silver clusters (AgNCs) generated by the electrochemical reduction.

Histone Cluster 2, H3a Antibody

20-abx129722 Abbexa
  • 467.00 EUR
  • 133.00 EUR
  • 1344.00 EUR
  • 634.00 EUR
  • 342.00 EUR
  • 100 ug
  • 10 ug
  • 1 mg
  • 200 ug
  • 50 ug

Histone Cluster 1, H1C Antibody

20-abx113027 Abbexa
  • 732.00 EUR
  • 398.00 EUR
  • 150 ul
  • 50 ul

Recombinant Histone Cluster 1, H2aa (HIST1H2AA)

4-RPN707Hu01 Cloud-Clone
  • 485.28 EUR
  • 233.00 EUR
  • 1544.80 EUR
  • 581.60 EUR
  • 1063.20 EUR
  • 388.00 EUR
  • 3712.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg

Recombinant Histone Cluster 1, H4a (HIST1H4A)

4-RPQ004Mi01 Cloud-Clone
  • 504.99 EUR
  • 238.00 EUR
  • 1618.72 EUR
  • 606.24 EUR
  • 1112.48 EUR
  • 401.00 EUR
  • 3896.80 EUR
  • 100 ug
  • 10ug
  • 1 mg
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  • 5 mg

Recombinant Histone Cluster 2, H2be (HIST2H2BE)

4-RPQ006Hu01 Cloud-Clone
  • 440.48 EUR
  • 221.00 EUR
  • 1376.80 EUR
  • 525.60 EUR
  • 951.20 EUR
  • 358.00 EUR
  • 3292.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
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  • 5 mg

Recombinant Histone Cluster 2, H2ac (HIST2H2AC)

4-RPQ018Hu01 Cloud-Clone
  • 476.32 EUR
  • 230.00 EUR
  • 1511.20 EUR
  • 570.40 EUR
  • 1040.80 EUR
  • 382.00 EUR
  • 3628.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
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  • 50ug
  • 5 mg

Recombinant Histone Cluster 2, H2aa3 (HIST2H2AA3)

4-RPQ019Hu01 Cloud-Clone
  • 490.66 EUR
  • 234.00 EUR
  • 1564.96 EUR
  • 588.32 EUR
  • 1076.64 EUR
  • 391.00 EUR
  • 3762.40 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg

Recombinant Histone Cluster 1, H2ab (HIST1H2AB)

4-RPQ021Hu01 Cloud-Clone
  • 474.53 EUR
  • 230.00 EUR
  • 1504.48 EUR
  • 568.16 EUR
  • 1036.32 EUR
  • 380.00 EUR
  • 3611.20 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
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  • 50ug
  • 5 mg

Recombinant Histone Cluster 1, H2ac (HIST1H2AC)

4-RPQ022Hu01 Cloud-Clone
  • 485.28 EUR
  • 233.00 EUR
  • 1544.80 EUR
  • 581.60 EUR
  • 1063.20 EUR
  • 388.00 EUR
  • 3712.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg

Recombinant Histone Cluster 1, H2ad (HIST1H2AD)

4-RPQ024Hu01 Cloud-Clone
  • 467.36 EUR
  • 228.00 EUR
  • 1477.60 EUR
  • 559.20 EUR
  • 1018.40 EUR
  • 376.00 EUR
  • 3544.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
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  • 50ug
  • 5 mg

Recombinant Histone Cluster 1, H2aj (HIST1H2AJ)

4-RPQ025Hu01 Cloud-Clone
  • 490.66 EUR
  • 234.00 EUR
  • 1564.96 EUR
  • 588.32 EUR
  • 1076.64 EUR
  • 391.00 EUR
  • 3762.40 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg

Recombinant Histone Cluster 2, H3a (HIST2H3A)

4-RPQ849Hu01 Cloud-Clone
  • 467.36 EUR
  • 228.00 EUR
  • 1477.60 EUR
  • 559.20 EUR
  • 1018.40 EUR
  • 376.00 EUR
  • 3544.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg

Recombinant Histone Cluster 2, H3a (HIST2H3A)

4-RPQ849Mu01 Cloud-Clone
  • 413.60 EUR
  • 214.00 EUR
  • 1276.00 EUR
  • 492.00 EUR
  • 884.00 EUR
  • 340.00 EUR
  • 3040.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
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  • 5 mg

Recombinant Histone Cluster 3, H2a (HIST3H2A)

4-RPQ850Hu01 Cloud-Clone
  • 490.66 EUR
  • 234.00 EUR
  • 1564.96 EUR
  • 588.32 EUR
  • 1076.64 EUR
  • 391.00 EUR
  • 3762.40 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg

Recombinant Histone Cluster 1, H2ag (HIST1H2AG)

4-RPS772Hu01 Cloud-Clone
  • 467.36 EUR
  • 228.00 EUR
  • 1477.60 EUR
  • 559.20 EUR
  • 1018.40 EUR
  • 376.00 EUR
  • 3544.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg

Recombinant Histone Cluster 1, H2ah (HIST1H2AH)

4-RPS773Hu01 Cloud-Clone
  • 485.28 EUR
  • 233.00 EUR
  • 1544.80 EUR
  • 581.60 EUR
  • 1063.20 EUR
  • 388.00 EUR
  • 3712.00 EUR
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg

Histone Cluster 2, H2ac (HIST2H2AC) Antibody

20-abx301208 Abbexa
  • 411.00 EUR
  • 1845.00 EUR
  • 599.00 EUR
  • 182.00 EUR
  • 300.00 EUR
  • 100 ug
  • 1 mg
  • 200 ug
  • 20 ug
  • 50 ug
The ECL signal generated by AgNCs can be utilized for HATs activities detection. The detection limit of the as-prepared ECL method was 0.49 nM (S/N = 3). The novel ECL method can be used for HATs activity analysis and inhibition in MCF-7 cell lysates which shows high promise in HATs-related clinical diagnostics.