Biology subjects

Furey, T.

Publications and source records attributed to Furey, T..

6 recordsLinked to original sources

bioRxiv2025

WAD: a wavelet-based linear programming method using L1-minimal reconstruction loss for accessible chromatin data deconvolution

Bulk tissue-based accessible chromatin studies provide summary annotations across all cell types within the tissue. These annotations can be skewed by varying proportions of individual cell types, especially in the context of disease studies. Estimated sample specific cell-type proportions can be used to mitigate effects of this variability while also addressing whether there exist significant alterations in cell proportions under certain conditions, like disease. We present WAD (Wavelet-based Accessible chromatin Deconvolution), a principled framework for robust estimation of cell type composition of bulk accessible chromatin data such as from the ATAC-seq assay. To determine informative reference cell profiles from single-cell accessible chromatin studies, WAD leverages wavelet-based denoising to suppress stochastic noise while preserving local chromatin continuity. Cell type proportion inference is reformulated as an L1-minimal linear programming problem, enabling scalable and interpretable solutions. Across 700 in silico pseudo-bulk mixtures generated from single-cell data, WAD achieved a consistently lower mean absolute error (MAE) and higher concordance (r > 0.85) than existing machine learning-based methods. These results demonstrate that wavelet-based feature extraction provides a biologically grounded and computationally efficient approach to chromatin signal deconvolution. A complete implementation of WAD is available at https://github.com/chae-jh/WAD.

bioinformatics↗

bioRxiv2023

ROCCO: A Robust Method for Detection of Open Chromatin via Convex Optimization

MotivationAnalysis of open chromatin regions across multiple samples from two or more distinct conditions can determine altered gene regulatory patterns associated with biological phenotypes and complex traits. The ATAC-seq assay allows for tractable genome-wide open chromatin profiling of large numbers of samples. Stable, broadly applicable genomic annotations of open chromatin regions are not available. Thus, most studies first identify open regions using peak calling methods for each sample independently. These are then heuristically combined to obtain a consensus peak set. Reconciling sample-specific peak results post hoc from larger cohorts is particularly challenging, and informative spatial features specific to open chromatin signals are not leveraged effectively. ResultsWe propose a novel method, ROCCO, that determines consensus open chromatin regions across multiple samples simultaneously. ROCCO employs robust summary statistics and solves a constrained optimization problem formulated to account for both enrichment and spatial dependence of open chromatin signal data. We show this formulation admits attractive theoretical and conceptual properties as well as superior empirical performance compared to current methodology. Availability and ImplementationSource code, documentation, and usage demos for ROCCO are available on GitHub at: https://github.com/nolan-h-hamilton/ROCCO. ROCCO can also be installed as a standalone binary utility using pip/PyPI. Contactnolanh@email.unc.edu or tsfurey@email.unc.edu. Supplementary InformationSupplementary material is available with this submission. Additional resources that may aid readers are available in the ROCCO GitHub repository.

bioinformatics↗

bioRxiv2023

CoVar: A generalizable machine learning approach to identify the coordinated regulators driving variational gene expression

Network inference is used to model transcriptional, signaling, and metabolic interactions among genes, proteins, and metabolites that identify biological pathways influencing disease pathogenesis. Advances in machine learning (ML)-based inference models exhibit the predictive capabilities of capturing latent patterns in genomic data. Such models are emerging as an alternative to the statistical models identifying causative factors driving complex diseases. We present CoVar, an inference framework that builds upon the properties of existing inference models, to find the central genes driving perturbed gene expression across biological states. We leverage ML-based network inference to find networks that capture the strength of regulatory interactions. Our model first pinpoints a subset of genes, termed variational, whose expression variabilities typify the differences in network connectivity between the control and perturbed data. Variational genes, by being differentially expressed themselves or possessing differentially expressed neighbor genes, capture gene expression variability. CoVar then creates subnetworks comprising variational genes and their strongly connected neighbor genes and identifies core genes central to these subnetworks that influence the bulk of the variational activity. Through the analysis of yeast expression data perturbed by the deletion of the mitochondrial genome, we show that CoVar identifies key genes not found through independent differential expression analysis.

genetics↗

bioRxiv2022

Aberrant miR-29 is a predictive feature of severe phenotypes in pediatric Crohn's disease

Crohns disease (CD) is a chronic inflammatory gut disorder. Molecular mechanisms underlying the clinical heterogeneity of CD remain poorly understood. MicroRNAs (miRNAs) are important regulators of gut physiology and several have been implicated in the pathogenesis of adult CD. However, there is a dearth of large-scale miRNA studies for pediatric CD. We hypothesized that specific miRNAs uniquely mark pediatric CD. We performed small RNA-sequencing of patient-matched non-inflamed colon and ileum biopsies from treatment-naive pediatric patients with CD (n=169) and a control cohort (n=108). Comprehensive miRNA analysis revealed 58 miRNAs altered in pediatric CD. Notably, multinomial logistic regression analysis revealed that index levels of ileal miR-29 are strongly predictive of severe inflammation and stricturing. Transcriptomic analyses of transgenic mice overexpressing miR-29 show a significant reduction of the tight junction protein gene Pmp22 and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we also found that pediatric CD patients with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels of PMP22. These findings strongly indicate that miR-29 up-regulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.

genomics↗

bioRxiv2021

BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis

IntroductionIn colitis, macrophage functionality is altered compared to homeostatic conditions. Loss of IL-10 signaling results in an inappropriate and chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice. MethodsWe performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of lipopolysaccharide (LPS) and with or without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization. ResultsTreatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in the attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo reduced severity of colitis as compared with vehicle-treated mice. ConclusionWe identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis. FundingThis work was funded in part through Helmsley Charitable Trust (SHARE Project 2), NIDDK P01DK094779, NIDDK 1R01DK104828, NIDDK P30-DK034987, NIDDK 1R01DK124617, NIH Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship (1F31DK122704), NIH T32 Genetics NIGMS Training Grant (T32-GM007092-43), NIH T32 Translational Medicine Training Grant (T32-GM122741), NIH T32 Gastroenterology Research Training Grant (T32-DK007737), and Crohns and Colitis Foundation Student Research Fellowship Award, and Gnotobiotic Animal Facility.

immunology↗

bioRxiv2020

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn's disease

Background and AimsThe host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohns disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. MethodsWe examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. ResultsColonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037). ConclusionIncreased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

genomics↗