Biology subjects

Veeravalli, S.

Publications and source records attributed to Veeravalli, S..

3 recordsLinked to original sources

bioRxiv2023

5-hydroxymethylcytosine profiling of cell-free DNA identifies bivalent genes that are prognostic of survival in high-risk neuroblastoma.

Neuroblastoma is the most common extra-cranial solid tumor in childhood and epigenetic dysregulation is a key driver of this embryonal disease. In cell-free DNA from neuroblastoma patients with high-risk disease, we found increased 5-hydroxymethylcytosine (5-hmC) deposition on Polycomb Repressive Complex 2 (PRC2) target genes, a finding previously described in the context of bivalent genes. As bivalent genes, defined as genes bearing both activating (H3K4me3) and repressive (H3K27me3) chromatin modifications, have been shown to play an important role in development and cancer, we investigated the potential role of bivalent genes in maintaining a de-differentiated state in neuroblastoma and their potential use as a biomarker. We identified 313 genes that bore bivalent chromatin marks, were enriched for mediators of neuronal differentiation, and were transcriptionally repressed across a panel of heterogenous neuroblastoma cell lines. Through gene set variance analysis, we developed a clinically implementable bivalent signature. In three distinct clinical cohorts, low bivalent signature was significantly and independently associated with worse clinical outcome in high-risk neuroblastoma patients. Thus, low expression of bivalent genes is a biomarker of ultra-high-risk disease and may represent a therapeutic opportunity in neuroblastoma.

genomics↗

bioRxiv2023

Metabolomic and transcriptomic analyses of Fmo5-/- mice reveal roles for flavin-containing monooxygenase 5 (FMO5) in NRF2-mediated oxidative stress, the unfolded protein response, lipid homeostasis, and carbohydrate and one-carbon metabolism

Flavin-containing monooxygenase 5 (FMO5) is a member of the FMO family of proteins best known for their roles in the detoxification of foreign chemicals and more recently in endogenous metabolism. We have previously shown that Fmo5-/- mice display an age-related lean phenotype, with much reduced weight gain from 20 weeks of age. The phenotype is characterized by decreased fat deposition, lower plasma concentrations of glucose and cholesterol, higher glucose tolerance and insulin sensitivity, and resistance to diet-induced obesity. In the present study we report the use of metabolomic and transcriptomic analyses of livers of Fmo5-/- and wild-type mice to identify factors underlying the lean phenotype of Fmo5-/- mice and gain insights into the function of FMO5. Disruption of the Fmo5 gene has wide-ranging effects on the abundance of metabolites and expression of genes in the liver. The results reveal that FMO5 is involved in upregulating the NRF2-mediated oxidative stress response, the unfolded protein response and response to hypoxia and cellular stress, indicating a role for the enzyme in adaptation to oxidative and metabolic stress. FMO5 also plays a role in stimulating a wide range of metabolic pathways and processes, particularly ones involved in the regulation of lipid homeostasis, the uptake and metabolism of glucose, the generation of cytosolic NADPH, and in one-carbon metabolism. The results predict that FMO5 acts by stimulating the NRF2, XBP1, PPARA and PPARG regulatory pathways, while inhibiting STAT1 and IRF7 pathways.

biochemistry↗

bioRxiv2019

FMO1 catalyzes the production of taurine from hypotaurine

Taurine is one of the most abundant amino acids in mammalian tissues. It is obtained from the diet and by de novo synthesis, from cysteic acid or hypotaurine. Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive. In large part this is due to the incorrect assignment, in 1962, of the enzyme as a NAD-dependent hypotaurine dehydrogenase. For more than 55 years the literature has continued to refer to this enzyme as such. Here we show, both in vivo and in vitro, that the enzyme that oxygenates hypotaurine to produce taurine is flavin-containing monooxygenase 1 (FMO1). Metabolite analysis of the urine of Fmo1-null mice by 1H NMR spectroscopy revealed a build-up of hypotaurine and a deficit of taurine in comparison with the concentrations of these compounds in the urine of wild-type mice. In vitro assays confirmed that FMO1 of human catalyzes the conversion of hypotaurine to taurine utilizing either NADPH or NADH as co-factor. FMO1 has a wide substrate range and is best known as a xenobiotic- or drug-metabolizing enzyme. The identification that the endogenous molecule hypotaurine is a substrate for the FMO1-catalyzed production of taurine resolves a long-standing mystery. This finding should help establish the role FMO1 plays in a range of biological processes in which taurine or its deficiency is implicated, including conjugation of bile acids, neurotransmitter, anti-oxidant and anti-inflammatory functions, the pathogenesis of obesity and skeletal muscle disorders.

biochemistry↗