Biology subjects

Mullins, A.

Publications and source records attributed to Mullins, A..

3 recordsLinked to original sources

bioRxiv2026

Spatial and functional mapping of the human pancreas reveals endocrine and exocrine cell states in health and metabolic disease

The human pancreas contains diverse endocrine and exocrine cell populations whose spatial organization is essential for tissue physiology. While single-cell and spatial transcriptomics revealed molecular heterogeneity across pancreatic cell types, linking these states to physiological activity in situ has remained challenging. Here, we combined single-nucleus RNA sequencing, spatial transcriptomics, and functional calcium imaging across pancreatic samples in health and metabolic disease. We identified heterogeneous endocrine and exocrine cell states associated with obesity and diabetes, including inflammatory remodeling of acinar and ductal populations. To directly couple tissue physiology with molecular state, we developed Slice-seq, which integrates calcium imaging with spatial transcriptomics in acute pancreatic slices. Slice-seq linked local endocrine composition and transcriptional programs with {beta} cell activity and identified extra-islet {beta} cells with reduced glucose responsiveness and mitochondrial oxidative metabolism. Together, our study provides a framework for linking pancreatic cell states to tissue organization and physiological activity in health and disease.

genomics↗

bioRxiv2026

MacroH2A-Mediated Gene Repression through Nucleosome Compaction and Remodeling Inhibition

MacroH2A (mH2A) is a histone variant primarily implicated in heterochromatin maintenance and transcriptional repression, yet how its conserved histone-fold and its variant-specific domains reshape chromatin to enforce gene silencing remains poorly understood. Here, we dissect the domain-specific contributions of mH2A to nucleosome dynamics and chromatin remodeling. We show that, in addition to its linker region, the C-terminal tail of mH2A histone-fold also stabilizes nucleosome entry/exit DNA. Cryo-EM analysis reveals that this C-terminus tracks along nucleosomal DNA toward the dyad, adopting an on-dyad binding mode reminiscent of linker histone H1. Additionally, the mH2A linker potently inhibits DNA translocation by both the INO80 and Chd1 chromatin remodelers, while the histone fold selectively suppresses INO80 activity. In contrast, the macro domain has no detectable impact on terminal DNA accessibility or remodeling. Together, our results uncover a previously unappreciated architectural role for the mH2A histone fold and establish the linker domain as a dominant regulator of nucleosome dynamics and chromatin remodeling, providing a mechanistic framework for how mH2A enforces transcriptional repression.

biochemistry↗

bioRxiv2020

Discovery and biosynthesis of gladiochelins: unusual lipodepsipeptide siderophores from Burkholderia gladioli

Burkholderia is a genus of diverse Gram-negative bacteria that includes several opportunistic pathogens. Siderophores, which transport iron from the environment into microbial cells, are important virulence factors in most pathogenic Burkholderia species. However, it is widely believed that Burkholderia gladioli, which can infect the lungs of cystic fibrosis (CF) sufferers, does not produce siderophores. B. gladioli BCC0238, isolated from the lung of a CF patient, produces two novel metabolites in a minimal medium containing glycerol and ribose as carbon sources. HPLC purification, followed by detailed spectroscopic analyses, identified these metabolites as unusual lipodepsipeptides containing a unique citrate-derived fatty acid and a rare dehydro-{beta}-alanine residue. The absolute configurations of the amino acid residues in the two metabolites was elucidated using Marfeys method and the gene cluster responsible for their biosynthesis was identified by bioinformatics and insertional mutagenesis. In-frame deletions and enzyme activity assays were used to investigate the functions of several proteins encoded by the biosynthetic gene cluster, which was found in the genomes of most B. gladioli isolates, suggesting that its metabolic products play an important role in the growth and/or survival of the species. The Chrome Azurol S (CAS) assay showed the metabolites bind ferric iron and that this supresses their production when added to the growth medium. Moreover, a gene encoding a TonB-dependent ferric-siderophore receptor is adjacent to the biosynthetic genes. Together, these observations suggest that these metabolites likely function as siderophores in B. gladioli.

microbiology↗