A5002078834- Genomics and Chromatin Dynamics
- Melanoma and MAPK Pathways
- Epigenetics and DNA Methylation
- Protein Kinase Regulation and GTPase Signaling
- Synthesis and biological activity
- RNA Research and Splicing
- Chromosomal and Genetic Variations
- Cancer-related gene regulation
- RNA modifications and cancer
- Developmental Biology and Gene Regulation
- Computational Drug Discovery Methods
- CRISPR and Genetic Engineering
- Cytokine Signaling Pathways and Interactions
- Neurobiology and Insect Physiology Research
- RNA and protein synthesis mechanisms
- Protease and Inhibitor Mechanisms
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Bone Metabolism and Diseases
- Ocular Oncology and Treatments
- Colorectal Cancer Treatments and Studies
- Plant Molecular Biology Research
- Animal Genetics and Reproduction
- Protein Degradation and Inhibitors
- Protein Structure and Dynamics
- Animal Behavior and Reproduction
University of North Carolina at Chapel Hill
2015-2024
The Royal Victorian Eye & Ear Hospital
2021-2024
Novartis (United States)
2024
Telesta Therapeutics (Canada)
2024
Australian National University
2022
University of Sheffield
2018
UNC Lineberger Comprehensive Cancer Center
2018
Pediatrics and Genetics
2018
TransCanada (Canada)
2006-2016
Novartis (Switzerland)
2014
The transition from a specified germ cell to population of pluripotent cells occurs rapidly following fertilization. During this developmental transition, the zygotic genome is largely transcriptionally quiescent and undergoes significant chromatin remodeling. In Drosophila , DNA-binding protein Zelda (also known as Vielfaltig) required for transcriptional activation genome. Open associated with Zelda-bound loci, well more generally regions active transcription. Nonetheless, extent which...
Calculations on phenol and a large number of phenols substituted with methyl, methoxyl, amino groups have yielded reliable gas-phase O−H bond dissociation energies, BDE(ArO−H)gas. Geometries for the phenol, ArOH, aryloxyl radical, ArO, were optimized at (semiempirical) AM1 level followed by single point density functional theory (DFT) calculations using 6-31G basis set supplemented p-functions hydrogen atom B3LYP functional. This gave BDE(PhO−H)gas = 86.46 kcal/mol, which is in good...
BRAF(V600E) mutations are found in 10% of colorectal cancers (CRCs). The low frequency this mutation therefore makes it a challenging target for drug development, unless subsets patients with higher rates can be defined. Knowledge the concordance between primary-metastasis pairs and impact on outcome would also assist optimal development. We selected primary CRCs from 525 (stages I-IV) evenly matched age (<70 ≥70), gender tumor location (right, left rectum), 81 pairs. BRAF(V600E), KRAS...
We examined how remote enhancers establish physical communication with target promoters to activate gene transcription in response environmental signals. Although the natural IFN-β enhancer is located immediately upstream of core promoter, it also can function as a classical element conferring virus infection-dependent activation heterologous promoters, even when placed several kilobases away from these promoters. demonstrated that “loops out” intervening DNA reach promoter. These chromatin...
Mutations at multiple sites in MEK1 occur cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated mutants and found they drove ERK signaling autonomously or a RAS/RAF-dependent manner. The latter are sensitive to feedback inhibition RAF, which limits functional output, often cooccur with RAS RAF mutations. They act as amplifiers signaling. In contrast, another class deletes hitherto unrecognized negative regulatory segment MEK1, is RAF-...
Specification of tissue identity during development requires precise coordination gene expression in both space and time. Spatially, master regulatory transcription factors are required to control tissue-specific programs. However, the mechanisms controlling how changes over time less well understood. Here, we show that hormone-induced temporal by regulating accessibility DNA elements. Using Drosophila wing, demonstrate accompanied genome-wide chromatin at temporal-specific enhancers. We...
The ecdysone pathway was among the first experimental systems employed to study impact of steroid hormones on genome. In Drosophila and other insects, coordinates developmental transitions, including wholesale transformation larva into adult during metamorphosis. Like hormones, controls gene expression through a nuclear receptor, which functions as ligand-dependent transcription factor. Although it is clear that elicits distinct transcriptional responses within its different target tissues,...
The histone locus body (HLB) assembles at replication-dependent genes and concentrates factors required for messenger RNA (mRNA) biosynthesis. FLASH (Flice-associated huge protein) U7 small nuclear RNP (snRNP) are HLB components that participate in 3′ processing of the nonpolyadenylated mRNAs by recruiting endonuclease CPSF-73 to pre-mRNA. Using transgenes complement a mutant, we show distinct domains involved snRNP binding, pre-mRNA cleavage, localization all proper function vivo. By...
Identification of biopolymer motifs represents a key step in the analysis biological sequences. The MEME Suite is widely used toolkit for comprehensive motifs; however, these tools are poorly integrated within popular frameworks like R/Bioconductor project, creating barriers to their use. Here we present memes, an R package that provides seamless interface selection tools. memes novel “data aware” tools, enabling rapid and complex discriminative motif workflows. In addition interfacing with...
Abstract The Von Hippel-Lindau Tumor Suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated HIF1-α, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule the HIF1-α binding pocket on pVHL and functions as molecular glue degrader of neosubstrate cysteine dioxygenase (CDO1) by recruiting it into VHL-cullin-ring complex selective CDO1 region involved in VHL recruitment was characterized through...
The homothorax ( hth ) gene of Drosophila melanogaster is required for executing Hox functions, head development, and forming the proximodistal (PD) axis appendages. We show that alternative splicing generates two types protein isoforms, one contains a DNA-binding homeodomain (HthFL) does not contain (HDless). Both Hth isoforms include evolutionarily conserved HM domain, which mediates direct interaction with Extradenticle (Exd), another protein. although both HthFL HDless can induce nuclear...
A defining feature of heterochromatin is methylation Lys9 histone H3 (H3K9me), a binding site for protein 1 (HP1). Although H3K9 methyltransferases and HP1 are necessary proper structure, the specific contribution to function animal development unknown. Using our recently developed platform engineer genes in Drosophila, we generated H3K9R mutant flies, separating functions nonhistone substrates methyltransferases. Nucleosome occupancy HP1a at pericentromeric markedly decreased mutants....
Like tissues of many organisms, Drosophila imaginal discs lose the ability to regenerate as they mature. This loss regenerative capacity coincides with reduced damage-responsive expression multiple genes needed for regeneration. We previously showed that two such genes, wg and Wnt6, are regulated by a single enhancer becomes progressively inactivated via Polycomb-mediated silencing mature (Harris et al., 2016). Here we explore generality this mechanism identify additional damage-responsive,...
Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe detail novel properties of the type II inhibitor, LXH254.LXH254 was profiled biochemical, vitro, and vivo assays, including examining activities drug a large panel cancer-derived cell lines comprehensive set models. In addition, activity LXH254 assessed cells where different sets paralogs were ablated, or that expressed kinase-impaired dimer-deficient variants ARAF.We an unexpected paralog selectivity...
Polycomb complexes regulate cell type–specific gene expression programs through heritable silencing of target genes. Trimethylation histone H3 lysine 27 (H3K27me3) is essential for this process. Perturbation H3K36 thought to interfere with H3K27me3. We show that mutants Drosophila replication-dependent ( H3.2 K36R ) or replication-independent H3.3 genes generally maintain and reach later stages development. In contrast, combined display widespread Hox misexpression fail develop past the...
This paper reports theoretical gas-phase structures and energetics using G2(MP2) theory for saturated oxygen chains of the general formula HOnH. Structural trends are discussed a simple hyperconjugation model which is capable giving qualitative explanation in bond lengths dihedral angles. Bond dissociation energies (BDEs) calculated increasing length, 49.9, 33.9, 17.8 kcal/mol H2O2, H2O3, H2O4, respectively. From an analysis radical stabilization energy fragments remaining after...