Biology subjects

Bond, M. L.

Publications and source records attributed to Bond, M. L..

7 recordsLinked to original sources

bioRxiv2024

Response eQTLs, chromatin accessibility, and 3D chromatin structure in chondrocytes provide mechanistic insight into osteoarthritis risk

Osteoarthritis (OA) poses a significant healthcare burden with limited treatment options. While genome-wide association studies (GWAS) have identified over 100 OA-associated loci, translating these findings into therapeutic targets remains challenging. Integrating expression quantitative trait loci (eQTL), 3D chromatin structure, and other genomic approaches with OA GWAS data offers a promising approach to elucidate disease mechanisms; however, comprehensive eQTL maps in OA-relevant tissues and conditions remain scarce. We mapped gene expression, chromatin accessibility, and 3D chromatin structure in primary human articular chondrocytes in both resting and OA-mimicking conditions. We identified thousands of differentially expressed genes, including those associated with differences in sex and age. RNA-seq in chondrocytes from 101 donors across two conditions uncovered 3782 unique eGenes, including 420 that exhibited strong and significant condition-specific effects. Colocalization with OA GWAS signals revealed 13 putative OA risk genes, 10 of which have not been previously identified. Chromatin accessibility and 3D chromatin structure provided insights into the mechanisms and conditional specificity of these variants. Our findings shed light on OA pathogenesis and highlight potential targets for therapeutic development. Highlights{circ} Comprehensive analysis of sex- and age-related global gene expression in human chondrocytes revealed differences that correlate with osteoarthritis {circ}First response eQTLs in chondrocytes treated with an OA-related stimulus {circ}Deeply sequenced Hi-C in resting and activated chondrocytes helps connect OA risk variants to their putative causal genes {circ}Colocalization analysis reveals 13 (including 10 novel) putative OA risk genes

genetics↗

bioRxiv2023

WNT activity reveals context-specific genetic effects on gene regulation in neural progenitors

Gene regulatory effects in bulk-post mortem brain tissues are undetected at many non-coding brain trait-associated loci. We hypothesized that context-specific genetic variant function during stimulation of a developmental signaling pathway would explain additional regulatory mechanisms. We measured chromatin accessibility and gene expression following activation of the canonical Wnt pathway in primary human neural progenitors from 82 donors. TCF/LEF motifs, brain structure-, and neuropsychiatric disorder-associated variants were enriched within Wnt-responsive regulatory elements (REs). Genetically influenced REs were enriched in genomic regions under positive selection along the human lineage. Stimulation of the Wnt pathway increased the detection of genetically influenced REs/genes by 66.2%/52.7%, and led to the identification of 397 REs primed for effects on gene expression. Context-specific molecular quantitative trait loci increased brain-trait colocalizations by up to 70%, suggesting that genetic variant effects during early neurodevelopmental patterning lead to differences in adult brain and behavioral traits.

genetics↗

bioRxiv2022

Chromatin loop dynamics during cellular differentiation are associated with changes to both anchor and internal regulatory features

3D chromatin structure has been shown to play a role in regulating gene transcription during biological transitions. While our understanding of loop formation and maintenance is rapidly improving, much less is known about the mechanisms driving changes in looping and the impact of differential looping on gene transcription. One limitation has been a lack of well powered differential looping data sets. To address this, we conducted a deeply sequenced Hi-C time course of megakaryocyte development comprising 4 biological replicates and 6 billion reads per time point. Statistical analysis revealed 1,503 differential loops. Gained loops were enriched for AP-1 occupancy and correlated with increased expression of genes at their anchors. Lost loops were characterized by increases in expression of genes within the loop boundaries. Linear modeling revealed that changes in histone H3 K27 acetylation, chromatin accessibility, and JUN binding in between the loop anchors were as predictive of changes in loop strength as changes to CTCF and/or cohesin occupancy at loop anchors. Finally, we built linear models and found that incorporating the dynamics of enhancer acetylation and loop strength increased accuracy of gene expression predictions.

genomics↗

bioRxiv2022

Temporal analysis suggests a reciprocal relationship between 3D chromatin structure and transcription

To infer potential causal relationships between 3D chromatin structure, enhancers, and gene transcription, we mapped each feature in a genome-wide fashion across eight narrowly-spaced timepoints of macrophage activation. Enhancers and genes connected by loops exhibited stronger correlations between histone H3K27 acetylation and expression than can be explained by genomic distance or physical proximity alone. Changes in acetylation at looped distal enhancers preceded changes in gene expression. Changes in gene expression exhibit a directional bias at differential loop anchors; gained loops are associated with increased expression of genes oriented away from the center of the loop, while lost loops were often accompanied by high levels of transcription with the loop boundaries themselves. Taken together, these results are consistent with a reciprocal relationship in which loops can facilitate increased transcription by connecting promoters to distal enhancers while high levels of transcription can impede loop formation. HIGHLIGHTSO_LILPS + IFN{gamma} triggers genome-wide changes in chromatin looping, enhancer acetylation, and gene expression C_LIO_LILooped enhancer-promoter pairs exhibit ordered and correlated changes in acetylation and expression C_LIO_LIChanges in gene expression exhibit a directional bias at differential loop anchors C_LIO_LILost loops are associated with high levels of transcription within loop boundaries C_LI

genomics↗

bioRxiv2021

Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems

Alzheimers disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (A{beta}) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that A{beta} is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e. microglia), which culminates in neuronal damage and cognitive decline. In order to test this hypothesis, many in vitro systems have been established to study A{beta}-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale. To address this, we used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic A{beta}. We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic A{beta} does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of A{beta} formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INF{gamma} activate microglia and induce transcriptional changes similar to those observed in disease associated microglia present in the AD brain, suggesting the potential suitability of this model to study AD-related neuroinflammation.

neuroscience↗

bioRxiv2019

CoralP: Flexible visualization of the human phosphatome

Protein phosphatases and kinases play critical roles in a host of biological processes and diseases via the removal and addition of phosphoryl groups. While kinases have been extensively studied for decades, recent findings regarding the specificity and activities of phosphatases have generated an increased interest in targeting phosphatases for pharmaceutical development. This increased focus has created a need for methods to visualize this important class of proteins within the context of the entire phosphatase protein family. Here, we present CoralP, an interactive web application for the generation of customizable, publication-quality representations of human phosphatome data. Phosphatase attributes can be encoded through edge colors, node colors, and node sizes. CoralP is the first and currently the only tool designed for phosphatome visualization and should be of great use to the signaling community. The source code and web application are available at https://github.com/PhanstielLab/coralp and http://phanstiel-lab.med.unc.edu/coralp respectively.

bioinformatics↗

bioRxiv2017

Seeing spots: Measuring, quantifying heritability, and assessing fitness consequences of coat pattern traits in a wild population of giraffes (Giraffa camelopardalis)

Polymorphic phenotypes of mammalian coat color have been important to the study of genetics and evolution, but little is known about the heritability and fitness consequences of variation in complex coat pattern traits in wild populations. Understanding the current evolution of coat patterns requires reliably measuring traits, quantifying heritability of the traits, and identifying the fitness consequences of specific phenotypes. Giraffe coat markings are highly variable and it has been hypothesized that variation in coat patterns most likely affects fitness by camouflaging neonates against predators. We quantified spot pattern traits of wild Masai giraffes using image analysis software, determined whether spot pattern traits were heritable, and assessed whether variation in heritable spot pattern traits was related to fitness as measured by juvenile survival. The methods we described comprise a framework for objective quantification of mammalian coat pattern traits based on photographic coat pattern data. We demonstrated that characteristics of giraffe coat spot shape are heritable. We did not find evidence for juvenile survival consequences of variation in spot traits, suggesting that spot traits are currently not under strong directional, disruptive, or stabilizing selection for neonate camouflage in our study population, but our sample size could not detect small differences in survival. Spot trait variation also may be more relevant to other components of fitness, such as adult survival or fecundity. We hope this case study will inspire further investigations of coat pattern traits.

evolutionary biology↗