Biology subjects

Hobbs, B.

Publications and source records attributed to Hobbs, B..

5 recordsLinked to original sources

bioRxiv2026

Identification of smoking-enabled blood miRNA regulatory networks

Cigarette smoking induces complex signaling disruptions that contribute to diseases such as COPD and lung cancer, yet the molecular mechanisms underlying these effects remain incompletely understood. To address this gap, we analyzed peripheral blood from 3190 COPDGene participants using LIONESS and PUMA and constructed miRNA-mRNA regulatory networks associated with smoking status. Comparing networks for active versus former smokers uncovered a striking shift in regulatory architecture: active smokers exhibited elevated miRNA targeting of the mitochondrial complex I protein NDUFA12. This finding was validated in lung tissue expression data from the Lung Genomics Research Consortium (LGRC), where we observed that ever-smokers showed consistent dysregulation of Ndufa12-targeting miRNAs compared to never-smokers. This allowed us to identify a set of smoking-defined circulating and tissue-associated miRNAs. To investigate the specific cellular compartment, we analyzed cell-type deconvoluted expression data from COPDGene blood and LTRC (Lung Tissue Research Consortium) lung tissue, as well as lung transcriptomics data from cigarette smoke-exposed mice, and identified the monocyte/macrophage compartment as a principal site of NDUFA12/Ndufa12 expression. Human THP-1 macrophages treated with cigarette smoke extract demonstrated selective inhibition of NDUFA12 by network-defined miRNAs. These distinct, NDUFA12-targeting, smoking-associated miRNA signatures, revealed through network analysis, describe new smoking-mitochondrial interactions that may serve as novel targets for therapeutic intervention.

Molecular Biology↗

bioRxiv2025

Accurate conformational ensembles of mixed folded proteins from NMR-guided simulations

Intrinsically disordered, low-complexity regions frequently cooperate with folded domains to mediate protein-protein interactions, yet accurately describing these mixed folded-disordered systems remains challenging. To visualize these mixed folded proteins, experimentally guided coarse-grained (CG) molecular dynamics simulations are often employed to extend the timescales required to capture the complex dynamics in play. However, the minimalistic nature of these approaches often compromises structural accuracy and can lead to inaccurate inter-domain interactions. Here we introduce backbone dihedral terms directly derived from NMR chemical shift data in CG-simulations to characterize the open state of a mixed-folded construct of the anti-aggregation chaperone DNAJB6 that contains a folded J-domain and a disordered GF linker. By tuning residue-specific backbone dihedral parameters to match NMR-derived secondary-structure propensities of the linker in CG-simulations, we generate conformational ensembles that yield accurate interdomain contact maps. In agreement with analysis of NMR relaxation data, the resulting ensembles show that even in the nominally open state the linker experiences motions that resemble those of the closed state driven by hydrophobic residues in GF. More generally we show that by expanding CG-simulations to allow them to capture both local and global structural properties, physically relevant interdomain contacts can be retrieved.

biophysics↗

bioRxiv2025

miRNA-mRNA network analysis identifies PAX5 as a potential regulator of adaptive immune response in COPD

Micro-ribonucleic acids (miRNAs) are key post-transcriptional regulators of the immune system and may play a role in Chronic Obstructive Pulmonary Disease (COPD). In this paper, we constructed subject-specific miRNA-mRNA regulatory networks using bulk and deconvoluted whole blood RNA-sequencing, whole blood miRNA-sequencing, and B-cell receptor-sequencing data from up to 570 miRNAs, 11,859 mRNAs, and 3,190 participants in the COPDGene study. Analysis of whole blood networks revealed two subnetworks of miRNA-mRNA interactions significantly (FDR<0.05) associated with changes in FEV1/FVC. We found that miRNAs (and mRNAs) in the network-identified groups had distinct expression patterns, with miRNAs (and mRNAs) in one group having overall higher expression in COPD (decreasing FEV1/FVC) and miRNAs (and mRNAs) in the other group having overall higher expression in controls (increasing FEV1/FVC). In addition, miRNAs (and mRNAs) within the same group were positively correlated, while those in different groups were negatively correlated, indicating distinct functional roles for these miRNAs (and mRNAs) as a function of increased COPD severity. Network analysis also identified PAX5, a transcription factor master regulator of B-cell development, as the main mRNA network hub. Using ChIP-seq data in lymphoblastoid cells, we identified a PAX5 binding site overlapping with a COPD genome-wide association signal in the promoter region of ADAM19. We also found a loss of co-expression between PAX5 and ADAM19 in COPD subjects. Furthermore, in B-cell deconvoluted data, PAX5 was differentially co-expressed with genes associated with B-cell activation and differentiation, revealing a possible mechanism for the regulation of the immune response in COPD. Finally, in B-cell receptor sequencing data, PAX5 and the identified mRNA subnetworks were negatively associated (FDR<0.05) with immunoglobulin class switching, and positively associated with IgM and IgD counts. In conclusion, PAX5 is a known regulator of B-cell identity. B cells are recognized as key players in chronic inflammation and immune dysregulation in COPD. Our work suggests that PAX5 plays a mediating role both in ADAM19 regulation and in miRNA regulation of early B cells in COPD.

systems biology↗

bioRxiv2025

A low-complexity linker as a driver of intra- and intermolecular interactions in DNAJB chaperones

J-domain proteins (JDPs) act as major regulators of the proteostasis network by driving the specificity of the Hsp70 machine. Their important functions are mediated by a low-complexity glycine-/phenylalanine-rich region (GF-linker) that links the folded J-domain with the substrate binding domain. Recently, we and others have shown that in an autoinhibited JDP state, an -helix formed within GF blocks the Hsp70 binding site on the J-domain. However, the role of the disordered GF-linker in autoinhibition and how the latter is released, are still not understood. Here, using autoinhibited DNAJB1 and DNAJB6 constructs, we show that in combination with the J-domain, the GF-linker creates a hydrophobic, partially collapsed cluster that shows a remarkable degree of allosteric communication, disruption of which can lead to destabilisation of autoinhibition. Apart from this crucial intramolecular role, we reveal that the GF-linker can also be recognised by the substrate-binding domain of Hsc70 and dictate the lifetime of the entire JDP-Hsc70 complex. Importantly, both the intra- and intermolecular GF-linker functions are DNAJB-class member-specific.

biophysics↗

bioRxiv2020

Singleton phage BlueFeather reveals novel relationships in the Arthrobacter phage population

Bacteriophages (phages) exhibit high genetic diversity, and the mosaic nature of the shared genetic pool makes quantifying phage relatedness a shifting target. Early parameters for clustering of related Mycobacteria and Arthrobacter phage genomes relied on nucleotide identity thresholds but, more recently, clustering of Gordonia and Microbacterium phages has been performed according to shared gene content. Singleton phages lack the nucleotide identity and/or shared gene content required for clustering newly sequenced genomes with known phages. Whole genome metrics of novel Arthrobacter phage BlueFeather, originally designated a putative singleton, showed low nucleotide identity but high amino acid and gene content similarity with Arthrobacter phages originally assigned to Clusters FE and FI. Gene content similarity revealed that BlueFeather shared genes with these phages in excess of the parameter for clustering Gordonia and Microbacterium phages. Single gene analyses revealed evidence of horizontal gene transfer between BlueFeather and phages in unique clusters that infect a variety of bacterial hosts. Our findings highlight the advantage of using shared gene content to study seemingly genetically isolated phages and have resulted in the reclustering of BlueFeather, a putative singleton, as well as former Cluster FI phages, into a newly expanded Cluster FE.

microbiology↗