A5003948093- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- NF-κB Signaling Pathways
- Cardiac Imaging and Diagnostics
- Bacterial Genetics and Biotechnology
- Immune Cell Function and Interaction
- Genetic Mapping and Diversity in Plants and Animals
- Bioinformatics and Genomic Networks
- Single-cell and spatial transcriptomics
- Immune Response and Inflammation
- Dermatology and Skin Diseases
- Neonatal skin health care
- Antimicrobial Resistance in Staphylococcus
- Advanced MRI Techniques and Applications
- Medical Imaging Techniques and Applications
- Gut microbiota and health
- Immune cells in cancer
- Advanced X-ray and CT Imaging
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Peroxisome Proliferator-Activated Receptors
- Neonatal Respiratory Health Research
- Polyamine Metabolism and Applications
- Mass Spectrometry Techniques and Applications
University of California, San Diego
2018-2024
Jacobs (United States)
2018-2024
National Human Genome Research Institute
2023
La Jolla Bioengineering Institute
2019-2021
Johns Hopkins Medicine
2016-2017
Johns Hopkins University
2016-2017
BD Biosciences (United States)
2002
Dalhousie University
1993-1996
Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation challenging. To better understand common associated with brain diseases, we defined noncoding regulatory regions for cell types the human brain. Whereas psychiatric disorders were primarily variants in transcriptional enhancers and promoters neurons, sporadic Alzheimer's disease (AD) largely confined to microglia enhancers. Interactome maps connecting disease-risk cell-type-specific revealed...
Macrophage activation is controlled by a balance between activating and inhibitory receptors
Prior exposure to microenvironmental signals could fundamentally change the response of macrophages subsequent stimuli. It is believed that T helper-2 (Th2)-cell-type cytokine interleukin-4 (IL-4) and Toll-like receptor (TLR) ligand-activated transcriptional programs mutually antagonize each other, no remarkable convergence has been identified between them. In contrast, here, we show IL-4-polarized established a hyperinflammatory gene expression program upon lipopolysaccharide (LPS)...
Abstract Spalt-like transcription factor 1 (SALL1) is a critical regulator of organogenesis and microglia identity. Here we demonstrate that disruption conserved microglia-specific super-enhancer interacting with the Sall1 promoter results in complete specific loss expression microglia. By determining genomic binding sites SALL1 leveraging enhancer knockout mice, provide evidence for functional interactions between SMAD4 required gene expression. binds directly to expression, consistent an...
Abstract Mechanisms by which members of the AP-1 family transcription factors play non-redundant biological roles despite recognizing same DNA sequence remain poorly understood. To address this question, here we investigate molecular functions and genome-wide binding patterns in primary immortalized mouse macrophages. ChIP-sequencing shows overlapping distinct profiles for each factor that were remodeled following TLR4 ligation. Development a machine learning approach jointly weighs hundreds...
Genetic variants in transcription factor motifs result divergent IL-4 responses macrophages from inbred strains of mice.
The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded receptors and other transcriptional repressors by deacetylation substrates. Recent studies provide evidence NCoR/HDAC3 complexes can also exert coactivator in brown adipocytes deacetylating activating PPARγ 1α (PGC1α) signaling via activator factor kappa-B (RANK) promotes the formation stable NCoR/HDAC3/PGC1β coactivates (NFκB)- protein 1...
Transcription factor-DNA interactions have been widely studied in the regulation of gene expression. We established an enzyme-linked immunoassay platform to quantify specific transcriptionfactor-DNA interactions. In our assay, dsDNA immobilized on a 96-well plate captures transcriptionfactor from nuclear extract mammalian cells. The DNA-bound transcription factor is detected and quantified by using factor-specific antibody. profiled multiple factors involved inflammation including NFkappaB...
Regulation of gene expression requires the combinatorial binding sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in spacing between TF sites can influence promoter enhancer activity. However, relative importance resulting from naturally occurring insertions deletions (InDels) has not been systematically analyzed. To address this question, we first characterized genome-wide relationships 73 TFs human K562 cells as determined by...
Abstract Background Metagenome-assembled genomes have greatly expanded the reference for skin microbiome. However, current are largely based on samples from adults in North America and lack representation infants individuals other continents. Results Here we use deep shotgun metagenomic sequencing to profile microbiota of 215 at age 2–3 months 12 who part VITALITY trial Australia as well 67 maternally matched samples. Based infant samples, present Early-Life Skin Genomes (ELSG) catalog,...
Abstract Motivation Genetic variation in regulatory elements can alter transcription factor (TF) binding by mutating a TF motif, which turn may affect the activity of elements. However, it is unclear motifs are prone to impact transcriptional regulation if mutated. Current motif analysis tools either prioritize TFs based on enrichment without linking function or limited their applications due assumption linearity between and functional effects. Results We present MAGGIE (Motif Alteration...
ABSTRACT CodY is a conserved broad-acting transcription factor that regulates the expression of genes related to amino acid metabolism and virulence in Gram-positive bacteria. Here, we performed first vivo determination target using novel monoclonal antibody methicillin-resistant Staphylococcus aureus (MRSA) USA300. Our results showed (i) same 135 promoter binding sites regulating 165 identified two closely virulent S. USA300 TCH1516 LAC strains; (ii) differential intensity for under...
We report the isolation of Vibrio harveyi acyl carrier protein (ACP) and cloning a 3,973-bp region containing fabG (encoding 3-ketoacyl-ACP reductase, 25.5 kDa), acpP ACP, 8.7 fabF synthase II, 43.1 pabC aminodeoxychorismate lyase, 29.9 kDa) genes. Predicted amino acid sequences were, respectively, 78, 86, 76, 35% identical to those corresponding Escherichia coli proteins. Five 11 sequence differences between V. E. ACP were nonconservative concentrated in loop helices I II.
A Vibrio harveyi enzyme which catalyzes the ATP-dependent ligation of fatty acids to acyl carrier protein (ACP) has been purified 6,000-fold apparent homogeneity by anion-exchange, gel filtration, and ACP-Sepharose affinity chromatography. Purified acyl-ACP synthetase migrated as a single 62-kDa band on sodium dodecyl sulfate-polyacrylamide electrophoresis an 80-kDa filtration under reducing conditions. Activity was lost within hours in absence glycerol low concentrations Triton X-100....
Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition the noncanonical IκB kinases TANK-binding kinase 1 IKKε with amlexanox restores insulin sensitivity glucose homeostasis in diabetic mice human patients. Here we report that improves diet-induced hypertriglyceridemia hypercholesterolemia Western diet-fed (WD-fed) Ldlr-/- protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, vascular dysfunction...
Abstract Unique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological psychiatric disorders. Here, we have defined active promoters for major types the human brain. Whereas disorders were primarily regulatory regions in neurons, idiopathic Alzheimer’s disease (AD) variants largely confined microglia enhancers. Interactome maps connecting GWAS gene revealed an extended...
We have developed a digitally synthesized patient which we call "Zach" (Zero millisecond Adjustable Clinical Heart) phantom, allows for an access to the ground truth and assessment of image-based cardiac functional analysis (CFA) using CT images with clinically realistic settings. The study Zach phantom revealed major problem CFA: "False dyssynchrony." Even though true motion wall segments is in synchrony, it may appear be dyssynchrony reconstructed images. It attributed how are locations...
Abstract CodY is a conserved broad acting transcription factor that regulates the expression of genes related to amino acid metabolism and virulence in methicillin-resistant Staphylococcus aureus (MRSA). target have been studied by using vitro DNA affinity purification deep sequencing (IDAP-Seq). Here we performed first vivo determination novel monoclonal antibody established ChIP-exo protocols. Our results showed, 1) same 135 promoter binding sites regulating 165 identified two closely...
To study the involvement of acyl carrier protein (ACP) in metabolism exogenous fatty acids Vibrio harveyi, cultures were incubated minimal medium with [9,10-3H]myristic acid, and labeled proteins analyzed by gel electrophoresis. Labeled acyl-ACP was positively identified immunoprecipitation anti-V. harveyi ACP serum comigration standards [3H]beta-alanine-labeled bands on both sodium dodecyl sulfate- urea-polyacrylamide gels. Surprisingly, most label corresponded to acid chain lengths less...
Cardiac motion (or functional) analysis has shown promise not only for non-invasive diagnosis of cardiovascular diseases but also prediction cardiac future events. Current imaging modalities limitations that could degrade the accuracy indices. In this paper, we present a projection-based estimation method x-ray CT estimates with high spatio-temporal resolution using projection data and reference 3D volume image. The experiment synthesized digital phantom showed promising results analysis.
For myocardial perfusion CT exams, beam hardening (BH) artifacts may degrade the accuracy of defect detection. Meanwhile, cardiac motion make BH process inconsistent, which makes conventional correction (BHC) methods ineffective. The aims this study were to assess severity and propose a projection-based iterative BHC method has potential handle motion-induced inconsistency better than methods. In study, four sets forward projection data first acquired using both cylindrical phantoms images...
Abstract Regulation of gene expression requires the combinatorial binding sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in spacing between TF sites can influence promoter enhancer activity. However, relative importance resulting from naturally occurring insertions deletions (InDels) has not been systematically analyzed. To address this question, we first characterized genome-wide relationships 75 TFs K562 cells as determined...
Previous studies have shown that the heritability of multiple brain-related traits and disorders is highly enriched in transcriptional enhancer regions. However, these regions often contain many individual variants, while only a subset them are likely to causally contribute trait. Statistical fine-mapping techniques can identify putative causal but their resolution limited, especially with variants high linkage disequilibrium. In cases, alternative computational methods estimate impact aid...
The complex interplay between microbiota and immunity is important to human health. To explore how altered adaptive influences the microbiome, we characterize skin, nares, gut of patients with recombination-activating gene (RAG) deficiency-a rare genetically defined inborn error (IEI) that results in a broad spectrum clinical phenotypes. Integrating de novo assembly metagenomes from RAG-deficient reference genome catalogs provides an expansive multi-kingdom view microbial diversity. patient...
ABSTRACT Mechanisms by which members of the AP-1 family transcription factors play both redundant and non-redundant biological roles despite recognizing same DNA sequence remain poorly understood. To address this question, we investigated molecular functions genome-wide binding patterns in macrophages. ChIP-sequencing showed overlapping distinct profiles for each factor that were remodeled following TLR4 ligation. Development a machine learning approach jointly weighs hundreds recognition...