A5023553117- Retinoids in leukemia and cellular processes
- Acute Myeloid Leukemia Research
- Genomics and Chromatin Dynamics
- Click Chemistry and Applications
- Advanced biosensing and bioanalysis techniques
- Epigenetics and DNA Methylation
- RNA Interference and Gene Delivery
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- DNA Repair Mechanisms
- Cancer Genomics and Diagnostics
- Chromosomal and Genetic Variations
- Cancer-related Molecular Pathways
- Cancer-related gene regulation
- RNA modifications and cancer
- Estrogen and related hormone effects
- Ferroptosis and cancer prognosis
- Advanced Breast Cancer Therapies
- Wnt/β-catenin signaling in development and cancer
- Neurobiology and Insect Physiology Research
- RNA Research and Splicing
- Prostate Cancer Treatment and Research
- Genomic variations and chromosomal abnormalities
- Genetic Associations and Epidemiology
- RNA and protein synthesis mechanisms
Bioscience (China)
2024
Duke University Hospital
2010-2019
Duke Medical Center
2010-2019
Duke University
2010-2019
Massachusetts Institute of Technology
2012-2015
Broad Institute
2014-2015
Vassar College
2015
Ansys (United States)
2015
IIT@MIT
2012
Dana-Farber Cancer Institute
2008
The reference human genome sequence set the stage for studies of genetic variation and its association with disease, but epigenomic lack a similar reference. To address this need, NIH Roadmap Epigenomics Consortium generated largest collection so far epigenomes primary cells tissues. Here we describe integrative analysis 111 as part programme, profiled histone modification patterns, DNA accessibility, methylation RNA expression. We establish global maps regulatory elements, define modules...
From Genome to Regulatory Networks For biologists, having a genome in hand is only the beginning—much more investigation still needed characterize how used help produce functional organism (see Perspective by Blaxter ). In this vein, Gerstein et al. (p. 1775 ) summarize for Caenorhabditis elegans genome, and The modENCODE Consortium 1787 Drosophila melanogaster full transcriptome analyses over developmental stages, genome-wide identification of transcription factor binding sites,...
The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Although R-loops normal transcriptional intermediates, they also associated with instability. Here, we show that BRCA1 is recruited form normally over a subset of transcription termination regions. There it mediates the recruitment specific, physiological binding partner, senataxin (SETX). Disruption this led R-loop-driven DNA damage at those loci as reflected by adjacent...
The origin recognition complex (ORC) specifies replication location. Saccharomyces cerevisiae ORC recognizes the ARS (autonomously replicating sequence) consensus sequence (ACS), but only a subset of potential genomic sites are bound, suggesting other chromosomal features influence binding. Using high-throughput sequencing to map binding and nucleosome positioning, we show that yeast origins characterized by an asymmetric pattern positioned nucleosomes flanking ACS. sequences sufficient...
DNA replication initiates from thousands of start sites throughout the Drosophila genome and must be coordinated with other ongoing nuclear processes such as transcription to ensure genetic epigenetic inheritance. Considerable progress has been made toward understanding how chromatin modifications regulate program; in contrast, we know relatively little about role landscape defining are selected regulated. Here, describe program context for multiple cell lines using data generated by...
Elevated expression of the orphan nuclear receptor estrogen-related α (ERRα) has been associated with a negative outcome in several cancers, although mechanism(s) by which this influences pathophysiology disease and how its activity is regulated remain unknown. Using chemical biology approach, it was determined that compounds, previously shown to inhibit canonical Wnt signaling, also inhibited transcriptional ERRα. The significance association revealed series biochemical genetic experiments...
We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These are defined by superenhancer (SE) maps, orthogonal to somatic mutations, distinct leukemic cell states. Examination transcriptional drivers for these epigenomic subtypes uncovers a subset particularly strong SE at retinoic acid receptor alpha (RARA) gene locus. The presence RARA concomitant high levels mRNA predisposes lines ex...
Abstract Background Structural rearrangements of the genome resulting in genic imbalance due to copy number change are often deleterious at organismal level, but common immortalized cell lines and tumors, where they may be an advantage cells. In order explore biological consequences changes Drosophila genome, we resequenced genomes 19 tissue-culture generated RNA-Seq profiles. Results Our work revealed dramatic duplications deletions all lines. We found three evidence indicating that were...
Precise DNA replication is crucial for genome maintenance, yet this process has been inherently difficult to study on a genome-wide level in untransformed differentiated metazoan cells. To determine how can be repressed, we examined regions selectively under-replicated Drosophila polytene salivary glands, and found they are transcriptionally silent enriched the repressive H3K27me3 mark. In first analysis of binding origin recognition complex (ORC) tissue, find that ORC dramatically reduced...
The origin recognition complex (ORC) binds to the specific positions on chromosomes that serve as DNA replication origins. Although ORC is conserved from yeast humans, sequence elements specify binding are not. In particular, metazoan shows no obvious specificity, whereas a within all Thus, chromatin must play an important role in ORC's ability recognize origins, it unclear whether plays of This study focused N-terminal bromo-adjacent homology domain Orc1 (Orc1BAH). Recent studies indicate...
We explore the role of DNA methylation in Alzheimer's disease (AD). To elucidate where falls along causal pathway linking risk factors to disease, we examine models assess its pathology AD. profiles were generated 740 brain samples using Illumina HumanMet450K beadset. focused our analysis on CpG sites from 11 AD susceptibility gene regions. The primary outcome was a quantitative measure neuritic amyloid plaque (NP), key early element pathology. tested four models: (1) independent...
FACT (facilitates chromatin transcription) consists of two essential subunits, Spt16 and Pob3, functions as a histone chaperone. Mutation spt16 results in global loss nucleosomes well aberrant transcription. Here, we show that the majority nucleosome changes upon depletion are alterations fuzziness position shift. Most nucleosomal suppressed by inhibition RNA polymerase II (Pol II) activity. Surprisingly, small subgroup is resistant to transcriptional inhibition. Notably, distinct...
A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid (AML) and ∼50% myelodysplastic syndromes (MDS). an actionable target for treatment tamibarotene, oral potent selective RARα agonist. Sensitivity to agonist tamibarotene was demonstrated RARA-high but not RARA-low preclinical AML models. The combination plus azacitidine evaluated a phase 2 clinical study 51 newly diagnosed unfit...
An analysis of mRNA expression in T47D breast cancer cells treated with the synthetic progestin R5020 revealed a subset progesterone receptor (PR) target genes that are enriched for E2F binding sites. Following up on this observation, we determined PR-B acts both direct and indirect manners to positively upregulate E2F1 cells. The effects PR were confirmed by chromatin immunoprecipitation (ChIP) analysis, which indicated agonist-bound was recruited several enhancer elements proximal...
Abstract BACKGROUND: Analysis of genomic alterations in circulating tumor DNA is gaining traction clinical oncology and can provide insights into biology without the need for invasive tissue sampling. In addition to genetic alterations, epigenomic reprogramming leads transcriptional dysregulation drives cancer phenotypes including molecular subtypes, histologic mechanisms resistance. As current liquid biopsy assays fail effectively capture biology, new approaches are needed examine status...
Abstract Background Using cDNA copies of transcripts and corresponding genomic sequences from the Berkeley Drosophila Genome Project, a set 24,753 donor acceptor splice sites were computed with scanning algorithm that tested for single nucleotide insertion, deletion substitution polymorphisms. this dataset, we developed progressive partitioning approach to examining effects challenging spliceosome system. Results Our analysis shows information content increases near flanking progressively...
Alterations in DNA methylation have been suggested to occur at a global, nuclear scale or certain loci the context of Alzheimer's disease. Here, leveraging new technology for profiling, we rigorously explore role brain's chromatin conformation pathophysiology disease (AD) on genome-wide scale. Clinical and post-mortem data come from two prospective clinical-pathologic cohort studies aging: Memory Aging Project Religious Order Study. Each subject is non-demented time entry. Post-mortem...
Abstract INTRODUCTION: Gastro-esophageal adenocarcinoma (GEA) is an aggressive and heterogeneous disease with a poor prognosis. Targeted therapies have failed largely due to challenges associated biopsy collection, tumor antigen heterogeneity, accurately distinguishing transcriptionally distinct esophageal, GE junction or gastric types. We developed novel, multimodal liquid assay that profiles genome-wide transcriptional activation. Here, we deploy this define clinically relevant insights in...