A5085730035- Chronic Lymphocytic Leukemia Research
- Epigenetics and DNA Methylation
- Lymphoma Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Glycosylation and Glycoproteins Research
- Immunodeficiency and Autoimmune Disorders
- Genomics and Chromatin Dynamics
- Advanced Breast Cancer Therapies
- RNA modifications and cancer
- Renal cell carcinoma treatment
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- Cancer-related gene regulation
- Renal and related cancers
- Pancreatic and Hepatic Oncology Research
- Genomics and Phylogenetic Studies
- Genomic variations and chromosomal abnormalities
- Glioma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Monoclonal and Polyclonal Antibodies Research
- Wnt/β-catenin signaling in development and cancer
- Immune Cell Function and Interaction
- Acute Lymphoblastic Leukemia research
- Genetics and Neurodevelopmental Disorders
- Genetic Associations and Epidemiology
Mayo Clinic in Arizona
2014-2025
Mayo Clinic
2016-2025
Mayo Clinic in Florida
2016-2024
WinnMed
2015-2020
Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics PDAC. Here we perform multi-parametric integrative analyses chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation epigenomic landscapes for PDAC which can predict their relative aggressiveness...
Abstract Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on availability relevant preclinical models. We have established a panel 96 glioblastoma patient-derived xenografts (PDX) undertaken its genomic phenotypic characterization. Experimental Design: PDXs were from glioblastoma, IDH-wildtype (n = 93), IDH-mutant 2), diffuse midline glioma, H3 K27M-mutant 1), both 60) recurrent 34) tumors. Tumor growth rates, histopathology,...
miRNAs play a key role in normal physiology and various diseases. miRNA profiling through next generation sequencing (miRNA-seq) has become the main platform for biological research biomarker discovery. However, analyzing data is challenging as it needs significant amount of computational resources bioinformatics expertise. Several web based analytical tools have been developed but they are limited to processing one or pair samples at time not suitable large scale study. Lack flexibility...
Perturbations in skeletal development and bone degeneration may result reduced mass quality, leading to greater fracture risk. Bone loss is mitigated by protective therapies, but there a clinical need for new bone-anabolic agents. Previous work has demonstrated that Ezh2 (enhancer of zeste homolog 2), histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation osteogenic progenitors. Here, we investigated whether inhibition can be leveraged stimulatory applications....
CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on residues. often overexpressed in human cancers. However, clinically applicable cancer therapeutic strategies based expression remain to be explored. Here, we report EZH2 inhibition effective CARM1-expressing epithelial ovarian cancer. Inhibition of activity using a small molecule inhibitor significantly suppresses the growth CARM1-expressing, but not CARM1-deficient, tumors two xenograft models and...
Abstract Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene Here, we explore the mechanistic role of super-enhancers linking TNFα amplification in AH. RNA-seq and histone modification ChIP-seq human explants show upregulation multiple CXCL chemokines Liver sinusoidal endothelial cells (LSEC) identified as an important...
Despite the considerable effort to characterize genomic landscape of chronic lymphocytic leukemia (CLL), published data have been almost exclusively derived from patients European Ancestry (EA), with significant underrepresentation minorities, including African (AA). To begin address this gap, we evaluated whether differences exist in genetic and transcriptomic features 157 AA 440 EA individuals diagnosed CLL. We sequenced 59 putative driver genes found an increased frequency high-impact...
Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified clear cell renal carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution 3 36 trimethylation (H3K36me3) ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine progressive and dysregulation occurs tumors, H3K36me3, copy number (CN) mRNA abundance was assessed two independent cohorts: ccRCC (n=71) Cancer Genome...
Here we provide evidence that RBBP4 modulates temozolomide (TMZ) sensitivity through coordinate regulation of two key DNA repair genes critical for recovery from TMZ-induced damage: methylguanine-DNA-methyltransferase (MGMT) and RAD51. Disruption enhanced TMZ sensitivity, induced synthetic lethality to PARP inhibition, increased damage signaling in response TMZ. Moreover, silencing H2AX phosphorylation apoptosis GBM cells. Intriguingly, knockdown suppressed the expression MGMT, RAD51, other...
Chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-Seq) has been widely used to identify genomic loci of transcription factor (TF) binding and histone modifications. ChIP-Seq data analysis involves multiple steps from read mapping peak calling integration interpretation. It remains challenging time-consuming process large amounts derived different antibodies or experimental designs using the same approach. To address this challenge, there is a need for...
ABSTRACT Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened small library of small-molecule modulators identify compounds capable inhibiting or reversing TGFβ-mediated activation. We identified pracinostat, an HDAC inhibitor, as potent attenuator lung and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic tissue. Mechanistically, found HDAC-dependent...
Adenosquamous cancer of the pancreas (ASCP) is a subtype pancreatic that has worse prognosis and greater metastatic potential than more common ductal adenocarcinoma (PDAC) subtype. To distinguish genomic landscape ASCP identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to series 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted fractions from these with whole-genome copy-number variant (CNV), whole-exome...
Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix to changes in phenotype are incompletely understood. Here, we evaluated effect on genome-wide chromatin accessibility freshly isolated lung fibroblasts using ATAC-seq. We found higher profoundly increased global relative lower stiffness, and these alterations were close genomic proximity known profibrotic gene programs. Motif analysis regulated loci identified ZNF416 as...
Abstract TP53 aberrations, including mutations and deletion of 17p13, are important adverse prognostic markers in chronic lymphocytic leukemia (CLL) but less studied high count monoclonal B-cell lymphocytosis (HCMBL), an asymptomatic pre-malignant stage CLL. Here we estimated the prevalence impact aberrations 1,230 newly diagnosed treatment-naïve individuals (849 CLL, 381 HCMBL). We defined state as: wild-type (no normal 17p), single-hit (del(17p) or one mutation), multi-hit (TP53 mutation...
Richter transformation (RT) represents the development of an aggressive lymphoma in chronic lymphocytic leukemia (CLL). Patients with RT and relapsed CLL have poor outcomes. Yet, extent molecular differences between two entities has not been fully explored. In this pilot study, we conducted RNA-seq targeted panel sequencing nodal tissues from 12 patients, including seven five CLL. Analysis data revealed major clusters, cluster C1 remaining all C2. Within C2, one ultimately developed RT; it...
Abstract Most disease-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWASs) reside in noncoding regions. There is increasing evidence that they play regulatory roles through epigenetic mechanisms altering local chromatin state, 3D structure, and looping interactions. We others have 42 CLL risk loci from GWASs. At 12 located outside of gene promoters, we previously demonstrated functional SNPs are highly enriched enhancers super-enhancers...
GATK Best Practices workflows are widely used in large-scale sequencing projects and recommend post-alignment processing before variant calling. Two key post-processing steps include the computationally intensive local realignment around known INDELs base quality score recalibration (BQSR). Both have been shown to reduce erroneous calls; however, findings mainly supported by analytical pipeline that incorporates BWA UnifiedGenotyper. It is not whether there any benefit of what extent might...
Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of total number CLL (i.e., tumor mutational load [TML]) or individually beyond international index (CLL-IPI) newly diagnosed and high-count monoclonal B-cell lymphocytosis (HC MBL). sequenced 59 among 557 individuals (112 HC MBL/445 CLL) a multi-stage design, to estimate hazard ratios (HR) 95% confidence intervals (CI) for time-to-first...
Epigenetic information encoded in covalent modifications of DNA and histone proteins regulates fundamental biological processes through the action chromatin regulators, transcription factors, noncoding RNA species. plasticity enables an organism to respond developmental environmental signals without genetic changes. However, aberrant epigenetic control plays a key role pathogenesis disease. Normal states could be disrupted by detrimental mutations expression alteration regulators or factors....
Abstract Background RBBP4 activates transcription by histone acetylation, but the partner acetyltransferases are unknown. Thus, we investigated hypothesis that interacts with p300 in a complex glioblastoma (GBM). Methods shRNA silencing of or and RNAseq was used to identify genes co-regulated GBM43 patient-derived xenograft (PDX). RBBP4/p300 demonstrated using proximity ligation assay (PLA) ChIPseq delineated H3 acetylation binding promoters/enhancers. Temozolomide (TMZ)-induced DNA double...
Significance Focal adhesion kinase (FAK) is an intensely studied protein involved in many medically relevant biological processes, including cancer. Despite the large interest FAK, a promising strategy to target FAK therapeutically elusive. Here, we show that region within contains autophosphorylation site tyrosine (Y) 397 essential for activity vivo. Myosin-1E (MYO1E), actin-dependent molecular motor protein, directly interacts with induce Y397 autophosphorylation, which, turn, causes...
Epigenetic dysregulation is involved in the etiology and progression of various human diseases. Formalin-fixed paraffin-embedded (FFPE) samples represent gold standard for archiving pathology samples, thus FFPE are a major resource clinical research. However, chromatin-based epigenetic assays settings limited to fresh or frozen hampered by low chromatin yield due lack reliable efficient preparation method. Here, we introduce new extraction method from tissues (Chrom-EX PE) assays.During...
We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a genome-wide association study (GWAS). To further elucidate genetic to DLBCL, we sought validate two 3q13.33 and 3p24.1 that were suggestive the original GWAS with additional genotyping. In meta-analysis (5662 cases 9237 controls) discovery scans three replication studies, locus (rs9831894; minor allele...