A5065478674- Sarcoma Diagnosis and Treatment
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- RNA Research and Splicing
- Genomics and Chromatin Dynamics
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- PARP inhibition in cancer therapy
- Histone Deacetylase Inhibitors Research
- Cancer-related molecular mechanisms research
- Gene expression and cancer classification
- Lymphoma Diagnosis and Treatment
- Cancer-related gene regulation
- Molecular Biology Techniques and Applications
- Cardiac tumors and thrombi
- Cancer, Hypoxia, and Metabolism
- Chromatin Remodeling and Cancer
- MicroRNA in disease regulation
- Bioinformatics and Genomic Networks
- Autophagy in Disease and Therapy
- Kruppel-like factors research
- Nutrition, Genetics, and Disease
- Genomics and Phylogenetic Studies
- Ubiquitin and proteasome pathways
- RNA and protein synthesis mechanisms
Nationwide Children's Hospital
2017-2025
The Ohio State University
2008-2024
The Ohio State University Wexner Medical Center
2015-2020
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
2011-2016
Sylvester Comprehensive Cancer Center
2016
Comprehensive Blood & Cancer Center
2015
U-M Rogel Cancer Center
2015
Chinese University of Hong Kong
2011
Cancer Genetics (United States)
2011
Baker Engineering (United States)
2009
Mapping the chromosomal locations of transcription factors, nucleosomes, histone modifications, chromatin remodeling enzymes, chaperones, and polymerases is one key tasks modern biology, as evidenced by Encyclopedia DNA Elements (ENCODE) Project. To this end, immunoprecipitation followed high-throughput sequencing (ChIP-seq) standard methodology. such protein-DNA interactions in vivo using ChIP-seq presents multiple challenges not only sample preparation but also for computational analysis....
Ewing sarcoma is a prototypical fusion transcription factor-associated pediatric cancer that expresses EWS/FLI or highly related FET/ETS chimera. dysregulates to induce and maintain sarcomagenesis, but the mechanisms utilized are not fully understood. We therefore sought define global effects of on chromatin conformation in cells using well-validated 'knock-down/rescue' model function combination with next generation sequencing assays evaluate how landscape changes loss, recovery,...
Abstract Transcription factors (TFs) are frequently mutated in cancer. Paediatric cancers exhibit few mutations genome-wide but harbour sentinel that affect TFs, which provides a context to precisely study the transcriptional circuits support mutant TF-driven oncogenesis. A broadly relevant mechanism has garnered intense focus involves ability of TFs hijack wild-type lineage-specific self-reinforcing circuits. However, it is not known whether this specific type circuitry equally crucial all...
Significance Ewing sarcoma is a pediatric bone malignancy driven by the fusion protein EWS/FLI. EWS/FLI mediates oncogenesis through its role as an aberrant transcription factor, but little known about molecular mechanisms underlying this function. We demonstrate in cells that activates gene targets binding at associated GGAA-microsatellites, and these repetitive sequences are necessary for cell proliferation anchorage-independent growth. Furthermore, we show previously unknown EWS portion...
Abstract Background Tumors are complex tissues containing collections of phenotypically diverse malignant and nonmalignant cells. We know little the mechanisms that govern heterogeneity tumor cells nor role plays in overcoming stresses, such as adaptation to different microenvironments. Osteosarcoma is an ideal model for studying these mechanisms—it exhibits widespread inter- intra-tumoral heterogeneity, predictable patterns metastasis, a lack clear targetable driver mutations. Understanding...
Abstract Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance gene silencing. Additional accumulation DNA methylation in target loci thought to cooperatively support this silencing during tumorigenesis. However, molecular mechanisms underlying complex interplay between two marks remain be explored. Here we show that activation PI3K/AKT signaling can trigger processing at many downstream genes. We also find acquired same cancer cells, thereby...
Breast cancer is more common in European Americans (EAs) than African (AAs) but mortality from breast higher among AAs. While there are racial differences DNA methylation and gene expression tumors, little known whether such exist tissues of healthy women. Genome-wide profiling was performed histologically normal Linear regression models were used to identify differentially-methylated CpG sites (CpGs) between EAs (n = 61) AAs 22). Correlations for assessed. Biological functions the genes...
Ewing sarcoma is a bone malignancy of children and young adults, frequently harboring the EWS/FLI chromosomal translocation. The resulting fusion protein an aberrant transcription factor that uses highly repetitive GGAA-containing elements (microsatellites) to activate repress thousands target genes mediating oncogenesis. However, mechanisms interaction with microsatellites regulation gene expression not clearly understood. Here, we profile genome-wide binding expression. Using combination...
Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting need to adopt novel approaches that specifically target drivers of sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed cell lines tumors, elevated expression levels associated worse overall...
Abstract Purpose: The successful clinical translation of compounds that target specific oncogenic transcription factors will require an understanding the mechanism suppression to optimize dose and schedule administration. We have previously shown trabectedin reverses gene signature EWS-FLI1 factor. In this report, we establish use it justify reevaluation drug in clinic patients with Ewing sarcoma. Experimental Design: demonstrate a novel epigenetic using biochemical fractionation chromatin...
Abstract Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and associated with arrested skeletal muscle differentiation. RMS poses considerable challenges in both diagnosis treatment, presence of fusion oncogenes predictive more aggressive forms disease. There a lack mechanistic understanding fusion-oncogene-driven tumorigenesis. Thus, efforts need to be directed toward defining fusion-oncogene biology identify novel therapeutic strategies improve clinical outcomes...
Abstract Motivation: Antibody-based Chromatin Immunoprecipitation assay followed by high-throughput sequencing technology (ChIP-seq) is a relatively new method to study the binding patterns of specific protein molecules over entire genome. ChIP-seq allows scientist get more comprehensive results in shorter time. Here, we present non-linear normalization algorithm and mixture modeling for comparing data from multiple samples characterizing genes based on their RNA polymerase II (Pol II)...
Abstract Ewing sarcoma is an aggressive bone cancer of children and young adults defined by the presence a chromosomal translocation: t(11;22)(q24;q12). The encoded protein, EWS/FLI, fuses amino-terminal domain EWS to carboxyl-terminus FLI. portion intrinsically disordered transcriptional regulatory domain, while FLI contains ETS DNA-binding two flanking regions unknown function. Early studies using non-Ewing models provided conflicting information on roles each in EWS/FLI oncogenic We...
EWS/FLI is the pathognomic fusion oncoprotein that drives Ewing sarcoma. The amino-terminal EWS portion coordinates transcriptional regulation and carboxy-terminal FLI contains an ETS DNA-binding domain. acts as aberrant transcription factor, orchestrating a complex mix of gene activation repression, from both high affinity motifs repetitive GGAA-microsatellites. Our overarching hypothesis executing multi-faceted requires to use distinct molecular mechanisms at different loci. Many attempts...
Many cancers are characterized by chromosomal translocations which result in the expression of oncogenic fusion transcription factors. Typically, these proteins contain an intrinsically disordered domain (IDD) fused with DNA-binding (DBD) another protein and orchestrate widespread transcriptional changes to promote malignancy. These fusions often sole recurring genomic aberration they cause, making them attractive therapeutic targets. However, targeting factors requires a better...
Paediatric cancers commonly harbour quiet mutational landscapes and are instead characterized by single driver events such as the mutation of critical chromatin regulators, expression oncohistones, or oncogenic fusion proteins. These ultimately promote malignancy through disruption normal gene regulation development. The protein in Ewing sarcoma, EWS/FLI, is an transcription factor that reshapes enhancer landscape, resulting widespread transcriptional dysregulation. Lysine-specific...
Recently, much attention has been given to elucidate how long-range gene regulation comes into play and histone modifications distal transcription factor binding contribute toward this mechanism. Androgen receptor (AR), a key regulator of prostate cancer, shown regulate its target genes via enhancers, leading the hypothesis global regulation. However, despite numerous flows newly generated data, precise mechanism with respect AR-mediated is still largely unknown. In study, we carried out an...
Single-nucleotide polymorphisms (SNPs) in one-carbon metabolism genes and lifestyle factors (alcohol drinking breast folate) may be determinants of whole-genome methylation the breast. DNA profiling was performed using Illumina Infinium HumanMethylation450 BeadChip 81 normal tissues from women undergoing reduction mammoplasty no history cancer. ANCOVA, adjusting for age, race body mass index, used to identify differentially methylated (DM) CpGs. Gene expression, by Affymetrix GeneChip Human...
Abstract Summary: Differential Identification using Mixtures Ensemble (DIME) is a package for identification of biologically significant differential binding sites between two conditions ChIP-seq data. It considers collection finite mixture models combined with false discovery rate (FDR) criterion to find statistically regions. This leads more reliable assessment based on statistical approach. In addition ChIP-seq, DIME also applicable data from other high-throughput platforms. Availability...
// Cenny Taslim 1 , Daniel Y. Weng Theodore M. Brasky Ramona G. Dumitrescu 2 Kun Huang Bhaskar V.S. Kallakury 3 Shiva Krishnan Adana A. Llanos 4 Catalin Marian 1, 11 Joseph McElroy 5 Sallie S. Schneider 6 Scott L. Spear 7 Melissa Troester 8 Jo Freudenheim 9 Susan Geyer 10 Peter Shields Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA Distilled Spirits Council of the United States, Washington, DC, Department Pathology, Georgetown Epidemiology, Rutgers New Brunswick,...
Abstract Ewing sarcoma is a pediatric bone cancer defined by chromosomal translocation fusing one of the FET family members to an ETS transcription factor. There have been seven reported translocations, with most recent over decade ago. We now report novel FET/ETS involving FUS and ETV4 detected in patient sarcoma. Here, we characterized FUS/ETV4 performing genomic localization transcriptional regulatory studies on numerous fusions cellular model. Through this comparative analysis,...
Abstract Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These changes are targeted novel lysine-specific demethylase-1 (LSD1) inhibitors, which currently in early-phase clinical trials. Single-agent–targeted therapy often induces resistance, and successful development requires knowledge resistance mechanisms, enabling design effective combination strategies. Here, we used a genome-scale...
Ewing sarcoma is the second most common bone cancer in children and young adults. In 85% of patients, a translocation between chromosomes 11 22 results potent fusion oncoprotein, EWSR1::FLI1. EWSR1::FLI1 only genetic alteration an otherwise unaltered genome tumors. The EWSR1 portion protein intrinsically disordered domain involved transcriptional regulation by FLI contains DNA binding shown to bind core GGAA motifs repeats. A small alpha-helix FLI1, DBD-𝛼4 helix, critical for transcription...