Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich''s ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.     

Hippocampal RNA sequencing in mice selectively bred for high and low activity

High and Low Activity strains of mice were bidirectionally selected for differences in open-field activity (DeFries et al., 1978, Behavior Genetics, 8: 3–13) and subsequently inbred to use as a genetic model for studying anxiety-like behaviors (Booher et al., 2021, Genes, Brain and Behavior, 20: e12730). Hippocampal RNA-sequencing of the High and Low Activity mice identified 3901 differentially expressed protein-coding genes, with both sex-dependent and sex-independent effects. Functional enrichment analysis (PANTHER) highlighted 15 gene ontology terms, which allowed us to create a narrow list of 264 top candidate genes. Of the top candidate genes, 46 encoded four Complexes (I, II, IV and V) and two electron carriers (cytochrome c and ubiquinone) of the mitochondrial oxidative phosphorylation process. The most striking results were in the female high anxiety, Low Activity mice, where 39/46 genes relating to oxidative phosphorylation were upregulated. In addition, comparison of our top candidate genes with two previously curated High and Low Activity gene lists highlight 24 overlapping genes, where Ndufa13, which encodes the supernumerary subunit A13 of complex I, was the only gene to be included in all three lists. Mitochondrial dysfunction has recently been implicated as both a cause and effect of anxiety-related disorders and thus should be further explored as a possible novel pharmaceutical treatment for anxiety disorders.     

Potential role of bacterial extracellular polymeric substances as biosorbent material for arsenic bioremediation

Carcinogenic effects of arsenic through consumption of contaminated water are an alarming threat and there is an emergent need to reduce extremely high levels of toxic arsenic from environment. Bacterial biofilms produce polyanionic extracellular polymeric substance (EPS) that is considered an excellent biosorbent material for the remediation of toxic metals and metalloids. This study was aimed to investigate the role of bacterial EPS in arsenic bioremediation. EPS was extracted from biofilm forming and arsenic reducer bacterial strains that were isolated from industrial waste water and characterized biochemically. Fourier transform infrared spectroscopy was also performed to study functional groups. Both Exiguobacterium profundum PT2 and Ochrobactrum ciceri SW1 exhibited enhanced EPS production in the presence of arsenic. Arsenic stress increased protein and carbohydrate contents in the EPS of both bacterial strains as indicated by the peaks of 1363 to 1613 and 1035 to 1218?cm^?1 wavenumbers, respectively to cope with arsenic present in the surroundings. Shifting of peaks in As⁵⁺ treated samples from 1363 to 1379, 847 to 800 and 1211 to 1134?cm^?1 demonstrated the involvement of proteins, carbohydrates and phosphates in the sequestration of arsenic. Scanning electron microscopic examination of EPS revealed structural alterations such as the presence of closely embedded large clumps with interstitial spaces between stacked layers of the EPS of E. profundum PT2 treated with As⁵⁺ displayed the enhanced polysaccharide content and arsenic sorption. Therefore, increased production of bacterial EPS with large number of polyanionic functional groups on its surface having tendency to sequester arsenic through electrostatic or covalent interactions presented EPS an excellent biosorbent material for arsenic bioremediation.     

Heat transfer analysis for EMHD peristalsis of ionic-nanofluids via curved channel with Joule dissipation and Hall effects

Journal of Biological Physics - The objective of this research is to study the combined influences of applied electric and magnetic fields on the two-phase peristaltic motion of nanofluid through a...