Biology subjects

Dan, W.

Publications and source records attributed to Dan, W..

3 recordsLinked to original sources

bioRxiv2025

Nuclear polysaccharides maintain H3K9me3-heterochromatin and genomic stability

Polysaccharides are known to be synthesized by enzymes in the endoplasmic reticulum and Golgi apparatus and transported through the secretory pathway to the cell surface or extracellular space1, where they mediate essential biological processes2-6. While classical localization and functions of polysaccharides are well established, their presence and potential roles in the nucleus remain unclear. Here, we demonstrate that N-glycans, a type of polysaccharides, are present in the cell nucleus and modify inner nuclear membrane (INM) proteins across diverse cell types--a modification referred to as N-linked glycosylation (N-glycosylation). N-glycosylation is enriched in chromatin regions marked by H3K9me3 and long interspersed nuclear element-1 (LINE-1) retrotransposons. N-glycosylation inhibition and INM protein N-glycosylation site mutation both downregulate H3K9me3 within lamina-associated domains (LADs) and lead to genomic instability. Mechanistically, N-glycosylation regulates the interaction between the histone H3K9 methyltransferase SETDB1 and INM proteins, promotes the association of SETDB1 with the INM, and maintains H3K9me3. Moreover, we reveal that canonical N-glycan biosynthetic machinery in ER contributes to the N-glycosylation of INM proteins. These findings uncover a previously unrecognized nuclear role for polysaccharides, broadening our understanding beyond their traditional subcellular distributions and functional profiles.

molecular biology↗

bioRxiv2023

The 3'UTR of vigR is required for virulence in Staphylococcus aureus and has expanded through STAR sequence repeat insertions

Staphylococcus aureus is an adaptable human pathogen causing life-threatening endocarditis and bacteraemia. Methicillin-resistant S. aureus (MRSA) is alarmingly common, and treatment is confined to last-line antibiotics. Vancomycin is the treatment of choice for MRSA bacteraemia and vancomycin treatment failure is often associated with vancomycin-intermediate S. aureus strains termed VISA. The regulatory 3 UTR of vigR mRNA contributes to vancomycin tolerance in the clinical VISA isolate JKD6008 and upregulates the lytic transglycosylase IsaA. Using MS2-affinity purification coupled with RNA sequencing (MAPS), we find that the vigR 3 UTR also interacts with mRNAs involved in carbon metabolism, amino acid biogenesis, cell wall biogenesis, and virulence. The vigR 3 UTR was found to repress dapE, a succinyl-diaminopimelate desuccinylase required for lysine and cell wall peptidoglycan synthesis, suggesting a broader role in controlling cell wall metabolism and vancomycin tolerance. Deletion of the vigR 3 UTR increased VISA virulence in a wax moth larvae model, and we find that an isaA mutant is completely attenuated in the larvae model. Sequence and structural analysis of the vigR 3 UTR indicates that the UTR has expanded through the acquisition of Staphylococcus aureus repeat insertions (STAR repeats) that partly contribute sequence for the isaA interaction seed and may functionalise the 3 UTR. Our findings reveal an extended regulatory network for vigR, uncovering a novel mechanism of regulation of cell wall metabolism and virulence in a clinical S. aureus isolate.

microbiology↗

bioRxiv2020

Androgen regulation of bowel function in mice and humans

Many digestive disorders have prominent sex differences in incidence, symptomatology, and treatment response that are not well understood. Irritable bowel syndrome (IBS), for example, affects approximately 10% of the population worldwide and tends to have different manifestations in males and females. Androgens are steroid hormones present at much higher levels in post-pubertal males than females and could be involved in these sex differences, but their normal functions in the bowel are largely unknown. Here, we show that gonadal androgens are required for normal gastrointestinal motility in vivo. In the healthy mouse gut, we detected androgen receptors in smooth muscle cells and a subset of enteric neurons. Surgical or genetic disruption of androgen signaling in adult mice selectively and reversibly altered colonic motility by affecting neurons rather than smooth muscle. To determine if androgens also influence human bowel function, we measured androgen levels in 208 adults with IBS. Free testosterone levels were lower in patients with IBS compared to healthy controls and inversely correlated with symptom severity. Taken together, these observations establish a role for androgens in the regulation of colonic motility and link altered androgen signaling with a common digestive disorder. These findings advance the fundamental understanding of gut motility, with implications for normal aging and disorders involving the gut-brain axis.

neuroscience↗