A5021221047- RNA Research and Splicing
- Prostate Cancer Treatment and Research
- Cancer Genomics and Diagnostics
- Single-cell and spatial transcriptomics
- Ubiquitin and proteasome pathways
- RNA Interference and Gene Delivery
- Protein Degradation and Inhibitors
- Genomics and Chromatin Dynamics
- Atherosclerosis and Cardiovascular Diseases
- Advanced biosensing and bioanalysis techniques
- Hippo pathway signaling and YAP/TAZ
- MicroRNA in disease regulation
- RNA modifications and cancer
- NF-κB Signaling Pathways
- Cancer Research and Treatments
- Epigenetics and DNA Methylation
- Veterinary Oncology Research
- interferon and immune responses
- Sarcoma Diagnosis and Treatment
- Nanoparticle-Based Drug Delivery
- Estrogen and related hormone effects
- Virus-based gene therapy research
- Cancer Cells and Metastasis
- Autophagy in Disease and Therapy
- Melanoma and MAPK Pathways
University of Michigan
2025
Stanford University
2023-2024
Lucile Packard Children's Hospital
2023-2024
Duke Medical Center
2018-2023
Duke University
2019-2022
Duke Cancer Institute
2019-2020
Women's College Hospital
2020
Institute for Clinical Evaluative Sciences
2020
Duke University Hospital
2019-2020
Pratt Institute
2019
Abstract Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation the impact of human genetic variation on disease 1–6 . Here we create evaluate a resource >13 million enhancer-gene regulatory interactions across 352 cell types tissues, by integrating predictive models, measurements chromatin state 3D contacts, large-scale perturbations generated ENCODE Consortium 7 We first systematic benchmarking pipeline to compare assembling dataset...
Enhancers are key drivers of gene regulation thought to act via 3D physical interactions with the promoters their target genes. However, genome-wide depletions architectural proteins such as cohesin result in only limited changes expression, despite a loss contact domains and loops. Consequently, role contacts enhancer function remains debated. Here, we developed CRISPRi regulatory elements upon degron operation (CRUDO), novel approach measure how frequency impact effects on genes by...
Abstract Sequence-specific activation by transcription factors is essential for gene regulation 1,2 . Key to this are domains, which often fall within disordered regions of 3,4 and recruit co-activators initiate 5 These interactions difficult characterize via most experimental techniques because they typically weak transient 6,7 Consequently, we know very little about whether these promiscuous or specific, the mechanisms binding, how tune strength activation. To address questions, developed...
Plastic waste has reached epidemic proportions worldwide, and the production of plastic continues to rise steadily. represents a diverse array commonly-used synthetic polymers that are extremely useful as durable, economically-beneficial alternatives other materials; however, despite wide-ranging utility plastic, increasing accumulation in environment had numerous detrimental impacts. In particular, marine debris can transport invasive species, entangle organisms, cause toxic chemical...
Abstract Despite a considerable expenditure of time and resources significant advances in experimental models disease, cancer research continues to suffer from extremely low success rates translating preclinical discoveries into clinical practice. The continued failure drug development, particularly late the course human testing, not only impacts patient outcomes, but also drives up cost for those therapies that do succeed. It is clear paradigm shift necessary if improvements this process...
Osteosarcoma (OS) is a lethal disease with few known targeted therapies. Here, we show that decreased ATRX expression associated more aggressive tumor cell phenotypes, including increased growth, migration, invasion, and metastasis. These phenotypic changes correspond activation of NF-κB signaling, extracellular matrix remodeling, integrin αvβ3 expression, ETS family transcription factor binding. characterize these in vitro, vivo, data set human OS patients. This aggression substantially...
Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis four cohorts discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, RAB6C) ADRA2A, IRX1 co-localized with expression quantitative trait (eQTLs), distal arteries. CRISPR gene editing further showed that ADRA2A NOS3 modified situ RNAscope clarified specificity of small vessels around capillaries skin. A functional...
Glioblastoma multiforme (GBM) is highly aggressive primary brain tumor with a 5-year survival rate of 7%. Previous studies have shown that GBM tumors reduced capacity to produce cholesterol and instead depend on the uptake produced by astrocytes. To target metabolism induce cancer cell death, synthetic high-density lipoprotein (sHDL) nanodiscs delivering Liver-X-Receptor (LXR) agonists CpG oligonucleotides for targeting were investigated. LXR synergize sHDL increasing expression ABCA1 are...
Mapping enhancer-gene (E-G) connections is critical for dissecting the functional impact of noncoding variants in human genome. Single-cell CRISPRi screens offer a powerful approach to identify these regulatory interactions, but existing methods such as Perturb-seq are limited by high sequencing costs and inefficient guide RNA capture across diverse cell types. Here, we decribe detailed protocol Direct-Capture Targeted (DC-TAP-seq) — cost-effective scalable that integrates TAP-seq1 with...
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with 5-year survival rate of 7%. Previous studies have shown that GBM tumors reduced capacity to produce cholesterol and instead depend on the uptake produced by astrocytes. To target metabolism induce cancer cell death, synthetic high-density lipoprotein (sHDL) nanodiscs delivering Liver-X-Receptor (LXR) agonists CpG oligonucleotides for targeting are investigated. LXR synergize sHDL increasing expression ABCA1 efflux...
Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models cancer offer a promising new approach identify treatments; however, for rare cancers, such as sarcomas, access patient samples limited, which precludes development patient-derived models. To address the limited samples, we have turned pet dogs naturally-occurring sarcomas. Although sarcomas make up less 1% all human represent 15%...
The evolution of therapeutic resistance is a major cause death for cancer patients. development therapy shaped by the ecological dynamics within tumor microenvironment and selective pressure host immune system. These forces often lead to evolutionary convergence on pathways or hallmarks that drive progression. Thus, deeper understanding convergences occur could reveal vulnerabilities treat therapy-resistant cancer. To this end, we combined phylogenetic clustering, systems biology analyses,...
Abstract Congenital heart defects (CHD) arise in part due to inherited genetic variants that alter genes and noncoding regulatory elements the human genome. These are thought act during fetal development influence formation of different structures. However, identifying genes, pathways, cell types mediate these effects has been challenging immense diversity involved as well superimposed complexities interpreting sequences. As such, understanding molecular functions both coding remains...
Abstract Mapping enhancers and their target genes in specific cell types is crucial for understanding gene regulation human disease genetics. However, accurately predicting enhancer-gene regulatory interactions from single-cell datasets has been challenging. Here, we introduce a new family of classification models, scE2G, to predict regulation. These models use features ATAC-seq or multiomic RNA data are trained on CRISPR perturbation dataset including >10,000 evaluated element-gene...
Summary Adaptation of cancer cells to targeted therapy follows ecological paradigms observed in natural populations that encounter resource depletion and changing environments, including activation pro-survival mechanisms, migration new locations, escape predation. We identified the p38 MAPK pathway as a common molecular driver these three responses during adaptation hormone resistance prostate cancer. The is activated therapy-resistant mechanistically drives convergent through sustained AR...
Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other cancers, treatment advances for osteosarcoma have stagnated, with little improvement survival the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples study biology of this complex disease.To overcome these barriers, we combined power comparative oncology patient-derived models high-throughput chemical screens...
Despite substantial improvements in the treatment landscape of prostate cancer, evolution hormone therapy-resistant and metastatic cancer remains a major cause cancer-related death globally. The mainstay for advanced is targeting androgen receptor signaling, including deprivation therapy plus second-generation blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or synthesis inhibition (abiraterone). While these agents have significantly prolonged lives patients with nearly...
Although genome wide association studies (GWAS) in large populations have identified hundreds of variants associated with common diseases such as coronary artery disease (CAD), most disease-associated lie within non-coding regions the genome, rendering it difficult to determine downstream causal gene and cell type. Here, we performed paired single nucleus expression chromatin accessibility profiling from 44 human arteries. To link molecular traits, developed a meta-map 88 samples discovered...
Case: A 15-year-old boy with chondroblastoma of the right hemipelvis presented significant periacetabular bone destruction. Neoadjuvant denosumab treatment facilitated initial joint preserving surgery. Unfortunately, he experienced 2 local recurrences and underwent wide surgical resection years after his diagnosis. Conclusion: Inhibition receptor activator NF-κB (RANK)/RANK ligand (RANK-L) pathway has been used neoadjuvantly for giant cell tumor bone, but its role in is less understood. This...
Abstract The evolution of therapeutic resistance is a major cause death for patients with solid tumors. development therapy shaped by the ecological dynamics within tumor microenvironment and selective pressure induced host immune system. These forces often lead to evolutionary convergence on one or more pathways hallmarks that drive progression. are, in turn, intimately linked each other through gene expression networks. Thus, deeper understanding convergences occur at level could reveal...
Abstract Purpose Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other cancers, treatment advances for osteosarcoma have stagnated, with little improvement survival the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples study biology of this complex disease. Experimental design To overcome these barriers, we combined power comparative oncology patient-derived...
Identifying target genes that are causally linked to coronary artery disease (CAD) remains an elusive problem despite the plethora of CAD genome-wide association study (GWAS) risk loci. Here, we performed single nucleus multiomic (RNA + ATAC) sequencing in 44 human arteries and bulk Hi-C 16 coronaries from multi-ethnic participants. From 126,804 nuclei, identified cell type specific transcriptional signatures, chromatin peaks, gene regulatory networks through peak linkage analysis....
Abstract Despite substantial improvements in the treatment landscape of prostate cancer, evolution hormone therapy-resistant and metastatic cancer remains a major cause cancer-related death globally. The mainstay for advanced is targeting androgen receptor signaling, including deprivation therapy plus second-generation blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or synthesis inhibition (abiraterone). While these agents have significantly prolonged lives patients with...