Histone H3 monoaminylations at Gln5 represent an important family of epigenetic marks in brain that have critical roles in permissive gene expression. We previously demonstrated that serotonylation and dopaminylation of Gln5 of histone H3 (H3Q5ser and H3Q5dop, respectively) are catalysed by transglutaminase 2 (TG2), and alter both local and global chromatin states. Here we found that TG2 additionally functions as an eraser and exchanger of H3 monoaminylations, including H3Q5 histaminylation (H3Q5his), which displays diurnally rhythmic expression in brain and contributes to circadian gene expression and behaviour.
View Article and Find Full Text PDFExtracellular vesicles (EVs) transport biomolecules that mediate intercellular communication. We previously showed that EVs contain DNA (EV-DNA) representing the entire genome. However, the mechanism of genomic EV-DNA packaging and its role in cancer remain elusive.
View Article and Find Full Text PDFThe RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. The model posits that nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). However, the extent to which DNMT1 relies on ubiquitin signaling through UHRF1 in support of DNA methylation maintenance remains unclear.
View Article and Find Full Text PDFGlycation, a non-enzymatic post-translational modification occurring on proteins, can be actively reversed via site-specific phosphorylation of the fructose-lysine moiety by FN3K kinase, to impact the cellular function of target protein. A regulatory axis between FN3K and glycated protein targets has been associated with conditions like diabetes and cancer. However the molecular basis of this relationship has not been explored so far.
View Article and Find Full Text PDFHistone proteins affect gene expression through multiple mechanisms, including through exchange with histone variants. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. Most notably, widely expressed variants of H2B remain elusive.
View Article and Find Full Text PDFChronic hepatitis B virus (HBV) infection is an incurable global health threat responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, Smc5/6.
View Article and Find Full Text PDFThe RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. Nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). Here, we profile contributions of UHRF1 and DNMT1 to genome-wide DNA methylation inheritance and dissect specific roles for ubiquitin signaling in this process.
View Article and Find Full Text PDFRegulation of histone proteins affects gene expression through multiple mechanisms including exchange with histone variants. However, widely expressed variants of H2B remain elusive. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain.
View Article and Find Full Text PDFNat Struct Mol Biol
January 2024
Here we investigate the role of epigenetics in the formation, transcription regulation, maintenance and termination of several non-canonical chromatin structures. Using two examples, we demonstrate how studying non-canonical structures may reveal underlying mechanisms with implications for disease and propose intriguing epigenetic avenues for further exploration.
View Article and Find Full Text PDFIntroduction: Negative pressure pulmonary edema (NPPE) is a potentially life-threatening complication that develops rapidly following acute upper airway obstruction. The condition is rare, dramatic but resolves quickly. Prompt recognition and appropriate supportive treatment may prevent unnecessary investigations and iatrogenic complications.
View Article and Find Full Text PDFOf great import for biochemistry articles is the inclusion of chemical structures in figures; they are common for showing reactions, detailing protein side chains and modifications, and depicting chemical probes. In this ninth installment of the TrendsTalk Special series: Scientific figure development, two scientists share their thoughts: what aspects do you consider when generating a figure that contains chemical structures? How do you decide how to represent the chemical/residue structure(s) (i.e.
View Article and Find Full Text PDFBackground: Oral breathing is considered to increase hyper-responsiveness of the airways. Data on the need for nose clip (NC) during exercise challenge test (ECT) in children and adolescents is scarce. Ouraim was to evaluate the role of NC during ECT in children and adolescents.
View Article and Find Full Text PDFChromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei and subsequent rupture of the micronuclear envelope profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed.
View Article and Find Full Text PDFEponemycin is an α,β-epoxyketone natural product that inhibits the proteasome covalent interaction of the epoxyketone warhead with catalytic N-terminal threonine residues. The epoxyketone warhead is biosynthesized from a β-ketoacid substrate by EpnF, a recently identified flavin-dependent acyl-CoA dehydrogenase-like enyzme. Herein, we report biochemical characterization of EpnF kinetics and substrate scope using a series of synthetic β-ketoacid substrates.
View Article and Find Full Text PDFThe ability to manipulate the chemical composition of proteins and peptides has been central to the development of improved polypeptide-based therapeutics and has enabled researchers to address fundamental biological questions that would otherwise be out of reach. Protein ligation, in which two or more polypeptides are covalently linked, is a powerful strategy for generating semisynthetic products and for controlling polypeptide topology. However, specialized tools are required to efficiently forge a peptide bond in a chemoselective manner with fast kinetics and high yield.
View Article and Find Full Text PDFRecent advances in protein engineering have provided a wealth of methods that allow for the site-specific manipulation of proteins and in cells. However, the efforts to expand these toolkits for use in live animals has been limited. Here, we report a new method for the semi-synthesis of site-specifically modified and chemically defined proteins in live animals.
View Article and Find Full Text PDFCancer cells undergo metabolic reprogramming to rely mostly on aerobic glycolysis (the Warburg effect). The increased glycolytic intake enhances the intracellular levels of reactive sugars and sugar metabolites. These reactive species can covalently modify macromolecules in a process termed glycation.
View Article and Find Full Text PDFForkhead box H1 (FoxH1) is an essential maternal pioneer factor during embryonic development that binds to specific GG/GT-containing DNA target sequences. Here we have determined high-resolution structures of three FoxH1 proteins (from human, frog and fish species) and four DNAs to clarify the way in which FoxH1 binds to these sites. We found that the protein-DNA interactions extend to both the minor and major DNA grooves and are thus almost twice as extensive as those of other FOX family members.
View Article and Find Full Text PDFBiochemical studies of integral membrane proteins are often hampered by low purification yields and technical limitations such as aggregation causing in vitro manipulations to be challenging. The ability of controlling proteins in live cells bypasses these limitations while broadening the scope of accessible questions owing to the proteins being in their native environment. Here we take advantage of the intein biorthogonality to mammalian systems, site specificity, fast kinetics, and auto-processing nature as an attractive option for modifying surface proteins.
View Article and Find Full Text PDFBiomolecular condensation constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that the co-condensation between transcription factors (TFs) and DNA can generate mechanical forces driving genome rearrangements. However, the reported forces generated by protein-DNA co-condensation are typically below one piconewton (pN), questioning its physiological significance.
View Article and Find Full Text PDFThe H1 linker histone family is the most abundant group of eukaryotic chromatin-binding proteins. However, their contribution to chromosome structure and function remains incompletely understood. Here we use single-molecule fluorescence and force microscopy to directly visualize the behavior of H1 on various nucleic acid and nucleosome substrates.
View Article and Find Full Text PDFBecause of their long half-lives and highly nucleophilic tails, histones are particularly susceptible to accumulating nonenzymatic covalent modifications, such as glycation. The resulting modifications can have profound effects on cellular physiology due to the regulatory role histones play in all DNA-templated processes; however, the complexity of Maillard chemistry on proteins makes tracking and enriching for glycated proteins a challenging task. Here, we characterize glyoxal (GO) modifications on histones using quantitative proteomics and an aniline-derived GO-reactive probe.
View Article and Find Full Text PDFInflammatory states are associated with anemia of chronic disease and acute infection. Hepcidin, a regulator of iron metabolism, is involved in iron pathophysiology during inflammation. We investigated biochemical characteristics in children with anemia from different causes.
View Article and Find Full Text PDFThe fidelity of the early embryonic program is underlined by tight regulation of the chromatin. Yet, how the chromatin is organized to prohibit the reversal of the developmental program remains unclear. Specifically, the totipotency-to-pluripotency transition marks one of the most dramatic events to the chromatin, and yet, the nature of histone alterations underlying this process is incompletely characterized.
View Article and Find Full Text PDFAs academia and industry push the boundaries of chemical biology more and more from basic science into impacting human health, we asked experts in the field what uniquely positions chemical biology as a translational science, how and when to maximize its potential, and where the field is headed. We also reflect personally on how chemical biology has impacted our careers in industry and academia.
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