A5082030263- Genomics and Chromatin Dynamics
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Genetic factors in colorectal cancer
- Cholangiocarcinoma and Gallbladder Cancer Studies
- DNA and Nucleic Acid Chemistry
- DNA Repair Mechanisms
- Epigenetics and DNA Methylation
- Gene expression and cancer classification
- Fungal and yeast genetics research
- Pancreatic and Hepatic Oncology Research
- CRISPR and Genetic Engineering
- Chromatin Remodeling and Cancer
- RNA modifications and cancer
- Plant Molecular Biology Research
- Cancer-related gene regulation
- Bacterial Genetics and Biotechnology
- Genomics and Phylogenetic Studies
- Genomics and Rare Diseases
- Cancer Genomics and Diagnostics
- Genetic Mapping and Diversity in Plants and Animals
- Animal Genetics and Reproduction
- Cytokine Signaling Pathways and Interactions
- Telomeres, Telomerase, and Senescence
- Invertebrate Immune Response Mechanisms
Duke University
2016-2025
University of Massachusetts Chan Medical School
2025
University of Southern California
2013-2024
Applied Genetic Technologies (United States)
2023
Duke University Hospital
2015-2022
Duke Medical Center
2015-2022
Center for Genomic Science
2015-2019
Laboratoire d'Informatique de Paris-Nord
2019
Brigham and Women's Hospital
2010-2016
Harvard University
2010-2016
Abstract Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters—fluke-positive (clusters 1/2) are enriched ERBB2 amplifications TP53 mutations; conversely, fluke-negative 3/4) exhibit copy-number alterations PD-1/PD-L2 or...
DNA sequence is a major determinant of the binding specificity transcription factors (TFs) for their genomic targets. However, eukaryotic cells often express, at same time, TFs with highly similar motifs but distinct in vivo Currently, it not well understood how seemingly identical achieve unique specificities vivo. Here, we used custom protein-binding microarrays to analyze TF putative sites context. Using yeast Cbf1 and Tye7 as our case studies, found that these bHLH (i.e., E-boxes) are...
Significance Genomes provide an abundance of putative binding sites for each transcription factor (TF). However, only small subsets these potential targets are functional. TFs the same protein family bind to target that very similar but not identical. This distinction allows closely related regulate different genes and thus execute distinct functions. Because nucleotide sequence core motif is often sufficient identifying a genomic target, we refined description TF by introducing combination...
Short tandem repeats (STRs) are enriched in eukaryotic cis-regulatory elements and alter gene expression, yet how they regulate transcription remains unknown. We found that STRs modulate factor (TF)-DNA affinities apparent on-rates by about 70-fold directly binding TF DNA-binding domains, with energetic impacts exceeding many consensus motif mutations. maximize the number of weakly preferred microstates near target sites, thereby increasing density, well predicted statistical mechanics....
The origin recognition complex (ORC) is an essential DNA replication initiation factor conserved in all eukaryotes. In Saccharomyces cerevisiae, ORC binds to specific elements; however, higher eukaryotes, exhibits little sequence specificity vitro or vivo. We investigated the genome-wide distribution of Drosophila and found that localizes chromosomal locations absence any discernible simple motif. Although no clear motif emerged, we were able use machine learning approaches accurately...
Transcriptional regulation is largely enacted by transcription factors (TFs) binding DNA. Large numbers of TF motifs have been revealed ChIP-chip experiments followed computational DNA motif discovery. However, the success discovery algorithms has limited when applied to sequences bound in vivo (such as those identified ChIP-chip) because observed TF-DNA interactions are not necessarily direct: Some TFs predominantly associate with indirectly through protein partners, while others exhibit...
Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences human transcription factors (TFs), but consequences such remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity used universal protein-binding microarrays assay sequence-specific across 41 reference 117 variant alleles found in individuals diverse ancestries families with Mendelian diseases. 77 28...
Abstract Transcription factor binding sites (TFBSs) are most commonly characterized by the nucleotide preferences at each position of DNA target. Whereas these sequence motifs quite accurate descriptions specificities transcription factors (TFs), proteins recognize as a three-dimensional object. structural features refine description TF and provide mechanistic insights into protein–DNA recognition. Existing motif databases contain extensive sequences identified in experiments based on their...
Transcription factors (TFs) play a central role in regulating gene expression by interacting with cis-regulatory DNA elements associated their target genes. Recent surveys have examined the binding specificities of most Saccharomyces cerevisiae TFs, but comprehensive evaluation data has been lacking.We analyzed vitro and vivo TF-DNA reported previous large-scale studies to generate comprehensive, curated resource specificity for all characterized S. TFs. Our collection comprises site motifs...
Significance Understanding molecular mechanisms of how regulatory proteins, called transcription factors (TFs), recognize their specific binding sites encoded into genomic DNA represents one the central, long-standing problems biophysics. Strikingly, our experiments demonstrate that context characterized by certain repeat symmetries surrounding TF significantly influences specificity. We expect results will impact understanding molecular, biophysical principles transcriptional regulation,...
The ELISA is the mainstay for sensitive and quantitative detection of protein analytes. Despite its utility, time-consuming, resource-intensive, infrastructure-dependent, limiting availability in resource-limited regions. Here, we describe a self-contained immunoassay platform (the "D4 assay") that converts sandwich into point-of-care test (POCT). D4 assay fabricated by inkjet printing reagents as microarrays on nanoscale polymer brushes glass chips, so all are "on-chip," these chips show...
The Myc-Max heterodimer is a transcription factor that regulates expression of large number genes. Genome occupancy thought to be driven by Enhancer box (E-box) DNA elements, CACGTG or variants, which the binds in vitro.
Although cell cycle control is an ancient, conserved, and essential process, some core animal fungal regulators share no more sequence identity than non-homologous proteins. Here, we show that evolution along the lineage was punctuated by early acquisition entrainment of SBF transcription factor through horizontal gene transfer. Cell in ancestor then proceeded a hybrid network containing both its ancestral counterpart E2F, which still maintained many basal fungi. We hypothesize...
Abstract Sequence-specific DNA-binding proteins (DBPs) play critical roles in biology and biotechnology, there has been considerable interest the engineering of DBPs with new or altered specificities for genome editing other applications. While some success reprogramming naturally occurring using selection methods, computational design that recognize arbitrary target sites remains an outstanding challenge. We describe a method small specific sequences through interactions bases major groove,...
Finding functional DNA binding sites of transcription factors (TFs) throughout the genome is a crucial step in understanding transcriptional regulation. Unfortunately, these are typically short and degenerate, posing significant statistical challenge: many more matches to known TF motifs occur than actually functional. However, information about chromatin structure may help identify sites. In particular, it has been shown that active regulatory regions usually depleted nucleosomes, thereby...
The DNA binding specificity of a transcription factor (TF) is typically represented using position weight matrix model, which implicitly assumes that individual bases in TF site contribute independently to the affinity, an assumption does not always hold. For this reason, more complex models have been developed. However, these their own caveats: they large number parameters, makes them hard learn and interpret.We propose novel regression-based TF-DNA specificity, trained high resolution...
Abstract Development of the malaria parasite, Plasmodium falciparum, is regulated by a limited number sequence-specific transcription factors (TFs). However, mechanisms which these TFs recognize genome-wide binding sites largely unknown. To address TF specificity, we investigated two subsets that either bind CACACA or GTGCAC DNA sequence motifs and further characterized additional ApiAP2 TFs, PfAP2-G PfAP2-EXP, unique (GTAC TGCATGCA). We also interrogated impact chromatin context on P....