Biology subjects

Gaffney, P.

Publications and source records attributed to Gaffney, P..

3 recordsLinked to original sources

bioRxiv2024

From Cardiac Myosin to the Beta Receptor: Autoantibodies Promote a Fibrotic Transcriptome and Reduced Ventricular Recovery in Human Myocarditis

BackgroundMyocarditis leads to dilated cardiomyopathy (DCM) with one-third failing to recover normal ejection fraction (EF50%), and there is a critical need for prognostic biomarkers to assess risk of nonrecovery. Cardiac myosin (CM) autoantibodies (AAbs) cross-reactive with the {beta}-adrenergic receptor ({beta}AR) are associated with myocarditis/DCM, but their potential for prognosis and functional relevance is not fully understood. MethodsCM AAbs and myocarditis-derived human monoclonal antibodies (mAbs) were investigated to define pathogenic mechanisms and CM epitopes of nonrecovery. Myocarditis patients who do not recover ejection fraction (EF<50%) by one year were studied in a longitudinal (n=41) cohort. Sera IgG and human mAbs were investigated for autoreactivity with CM and CM peptides by ELISA, protein kinase A (PKA) activation, and transcriptomic analysis in H9c2 heart cell line. ResultsCM AAbs were significantly elevated in nonrecovered compared to recovered patients and correlated with reduced EF (<50%). CM epitopes specific to nonrecovery were identified. Transcriptomic analysis revealed serum IgG and mAb 2C.4 induced fibrosis/apoptosis pathways in vitro similar to isoproterenol treated cells. Sera IgG and 2C.4 activated PKA in an IgG and {beta}AR-dependent manner. Endomyocardial biopsies from myocarditis/DCM revealed IgG+ trichrome+ tissues. ConclusionsCM AAbs were significantly elevated in nonrecovered patients, suggesting novel prognostic relevance. CM AAbs correlated with lower EF, and Ab-induced fibrosis/apoptosis pathways suggested a role for CM AAbs in patients who do not recover and develop irreversible heart failure. Homology between CM and {beta}ARs supports mechanisms related to cross-reactivity of CM AAbs with the {beta}AR, a potential AAb target in nonrecovery.

immunology↗

bioRxiv2020

An active chromatin interactome elucidates the biological mechanisms underlying genetic risk factors of dermatological conditions in disease relevant cell lines

Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. Here we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis, psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis associated risk loci. For example, the variant rs10794648, which is generally assigned to IFNLR1, was linked to GRHL3 in our dataset, a gene essential in skin repair and development. Our findings, therefore, indicate a renewed importance of skin related factors in the risk of disease. O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/973271v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@99cd40org.highwire.dtl.DTLVardef@1725b6dorg.highwire.dtl.DTLVardef@d05d21org.highwire.dtl.DTLVardef@1924d07_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract In this article we take disease associated variants from 5 dermatological conditions and use cell type specific datasets to map genes that could be affected by these variants, providing insight into disease mechanisms. C_FIG

genomics↗

bioRxiv2019

Chromatin-based techniques map DNA interaction landscapes in psoriasis susceptibility loci and highlight KLF4 as a target gene in 9q31

Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. Here, we use a disease-focused Capture Hi-C experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. In the 9q31 risk locus we combine further epigenomic evidence to demonstrate how the psoriasis association forms a functional interaction with the distant (>500 kb) KLF4 gene. We use CRISPR activation coupled with RNA-seq to demonstrate how activation of psoriasis-associated enhancers upregulates KLF4 in HaCaT cells. Our study design provides a robust pipeline for following up on GWAS disease-associated variants, paving the way for functional translation of genetic findings into clinical benefit.

genomics↗