txci-ATAC-seq: a massive-scale single-cell technique to profile chromatin accessibility.

We develop a large-scale single-cell ATAC-seq method by combining Tn5-based pre-indexing with 10× Genomics barcoding, enabling the indexing of up to 200,000 nuclei across multiple samples in a single reaction. We profile 449,953 nuclei across diverse tissues, including the human cortex, mouse brain, human lung, mouse lung, mouse liver, and lung tissue from a club cell secretory protein knockout (CC16-/-) model. Our study of CC16-/- nuclei uncovers previously underappreciated technical artifacts derived from remnant 129 mouse strain genetic material, which cause profound cell-type-specific changes in regulatory elements near many genes, thereby confounding the interpretation of this commonly referenced mouse model.

Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in Caenorhabditis elegans.

The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food ubiquitously, from the baking industry to our everyday lives. However, the Maillard reaction also occurs in all cells, from prokaryotes to eukaryotes, forming advanced glycation end-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNAseq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGE (MG-H1)-induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream regulator for increased feeding upon accumulation of AGEs by partially controlling the expression of tdc-1 gene. Furthermore, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MG-H1 AGE. Understanding this signaling pathway may help understand hedonistic overfeeding behavior observed due to modern AGE-rich diets.

The Human Glyoxalase Gene Family in Health and Disease.

The glyoxalase gene family consists of six structurally and functionally diverse enzymes with broad roles in metabolism. The common feature that defines this family is based on structural motifs that coordinate divalent cations which are required for activity. These family members have been implicated in a variety of physiological processes, including amino-acid metabolism (4-hydroxyphenylpyruvate dioxygenase; HPD), primary metabolism (methylmalonyl-CoA epimerase; MCEE), and aldehyde detoxication (glyoxalase 1; GLO1) and therefore have significant associations with disease. A central function of this family is the detoxification of reactive dicarbonyls (e.g., methylglyoxal), which react with cellular nucleophiles, resulting in the modification of lipids, proteins, and DNA. These damaging modifications activate canonical stress responses such as heat shock, unfolded protein, antioxidant, and DNA damage responses. Thus, glyoxalases serve an important role in homeostasis, preventing the pathogenesis of metabolic disease states, including obesity, diabetes, cardiovascular disease, renal failure, and aging. This review presents a thorough overview of the literature surrounding this diverse enzyme class. Although extensive literature exists for some members of this family (e.g., GLO1), little is known about the physiological role of glyoxalase domain-containing protein 4 (GLOD4) and 5 (GLOD5), paving the way for exciting avenues for future research.