A5102961421- RNA Research and Splicing
- RNA modifications and cancer
- Muscle Physiology and Disorders
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Protein Degradation and Inhibitors
- Hemoglobinopathies and Related Disorders
- Chromatin Remodeling and Cancer
- RNA regulation and disease
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Genetic Neurodegenerative Diseases
- Advanced Semiconductor Detectors and Materials
- Telomeres, Telomerase, and Senescence
- Blood groups and transfusion
- Acute Myeloid Leukemia Research
- Cardiomyopathy and Myosin Studies
- Forest Insect Ecology and Management
- Prenatal Screening and Diagnostics
- Chromosomal and Genetic Variations
- Cancer Genomics and Diagnostics
- Mesenchymal stem cell research
- Multiple Myeloma Research and Treatments
- Neurogenetic and Muscular Disorders Research
- Silk-based biomaterials and applications
University of Colorado Anschutz Medical Campus
2021-2024
Fred Hutch Cancer Center
2017-2020
Saint Louis University
2019
University of Rochester Medical Center
2019
Ultragenyx Pharmaceutical (United States)
2019
University of Washington
2019
Children's Hospital of Philadelphia
1994-2018
University of Pennsylvania
2010-2018
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2017
Cancer Research Center
2017
Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia require the mammalian SWI/SNF remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known suppress tumor formation in several cell types, found instead rely Brg1 support oncogenic transcriptional program, which includes Myc as one its key targets. To account this context-specific function, identify...
Acetylation of histones triggers association with bromodomain-containing proteins that regulate diverse chromatin-related processes. Although acetylation transcription factors has been appreciated for some time, the mechanistic consequences are less well understood. The hematopoietic factor GATA1 is acetylated at conserved lysines required its stable chromatin. We show BET family protein Brd3 binds via first bromodomain (BD1) to in an acetylation-dependent manner vitro and vivo. Mutation a...
Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of DUX4 gene, transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible FSHD, better understanding relationship between activity, muscle pathology and magnetic resonance imaging (MRI) changes crucial both to understand mechanisms for design future clinical trials. Here, we performed MRIs lower extremities 36 individuals with...
Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of DUX4 in skeletal muscle cells. a transcription factor that activates genes normally associated with stem cell biology and its FSHD cells results apoptosis. To identify pathways necessary for DUX4-mediated apoptosis, we performed an siRNA screen RD rhabdomyosarcoma line inducible transgene. Our identified components MYC-mediated apoptotic pathway double-stranded RNA (dsRNA) innate immune response as mediators DUX4-induced...
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by misexpression of the double homeobox 4 (DUX4) developmental transcription factor in mature skeletal muscle, where it responsible for muscle degeneration. Preventing expression DUX4 mRNA a disease-modifying therapeutic strategy with potential to halt or reverse course disease. We previously reported that agonists
Germline GATA1 mutations that result in the production of an amino-truncated protein termed GATA1s (where s indicates short) cause congenital hypoplastic anemia. In patients with trisomy 21, similar somatic GATA1s-producing promote transient myeloproliferative disease and acute megakaryoblastic leukemia. Here, we demonstrate induced pluripotent stem cells (iPSCs) from GATA1-truncating exhibit impaired erythroid potential, but enhanced megakaryopoiesis myelopoiesis, recapitulating major...
Abstract Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to discovery candidate therapeutics, and it is important identify markers disease activity inform clinical trial design. For drugs that inhibit DUX4 expression, measuring or DUX4-target gene expression might be an interim measure drug activity; however, only a subset FHSD muscle biopsies shows evidence expression. Our prior study showed MRI T2-STIR-positive muscles had higher probability...
Abstract Nonsense-mediated mRNA decay (NMD) is a network of pathways that degrades transcripts undergo premature translation termination. In mammals, NMD can be divided into the exon junction complex (EJC)-enhanced and EJC-independent branches. Fluorescence- luminescence-based reporters have long been effective tools to investigate NMD, yet existing largely focus on EJC-enhanced pathway. Here, we present system for comparative studies NMD. This also enables study NMD-associated outcomes such...
Self-reinforcing negative feedback loops are commonly observed in biological systems. RNA-mediated have been described the formation of heterochromatin at centromeres fission yeast and inactive X chromosome mammalian cells. The telomere repeat-containing RNA (TERRA) has also implicated telomeric through a self-reinforcing loop. In cells derived from human ICF syndrome, TERRA levels abnormally elevated telomeres shortened. We now show that is abnormal propose fail to reinforce TERRA-dependent...
Members of the bromodomain and extra-terminal domain (BET) family proteins (bromodomain-containing (BRD) 2, 3, 4, T) are widely expressed highly conserved regulators gene expression in eukaryotes. These have been intimately linked to human disease, more than a dozen clinical trials currently underway test BET-protein inhibitors as modulators cancer. However, although it is clear that these use their bromodomains bind both histones transcription factors bearing acetylated lysine residues,...
Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs enhance repression DUX4 prevent its expression cells therefore represent candidate therapies for FSHD.We screened an aggregated chemical library enriched compounds with activities Pharmakon 1600 composed have reached clinical testing identify molecules decrease as monitored...
The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. normally expressed cleavage-stage embryo, whereas chromatin repression prevents expression most somatic tissues. Failure this causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression skeletal muscle. In study, we used CRISPR/Cas9 engineered immunoprecipitation (enChIP) locus-specific proteomics characterize D4Z4-associated proteins. These and other approaches...
DUX4 activates the first wave of zygotic gene expression in early embryo. Mis-expression skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas cancers suppresses IFNγ induction major histocompatibility complex class I (MHC I) and contributes to immune evasion. We show that protein interacts with STAT1 broadly IFNγ-stimulated genes by decreasing bound Pol-II recruitment. Transcriptional suppression interferon-stimulated (ISGs) requires conserved (L)LxxL(L) motifs...
Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss results in widespread production proteins unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition upon expression disease-causing transcription factor, DUX4. Using a cell-based model FSHD, we show from physiological targets and find that RNA-binding are...
The DUX4 transcription factor is normally expressed in the cleavage-stage embryo and regulates genes involved embryonic genome activation. Misexpression of skeletal muscle, however, toxic causes facioscapulohumeral muscular dystrophy (FSHD). We recently showed DUX4-induced toxicity due, part, to activation double-stranded RNA (dsRNA) response pathway accumulation intranuclear dsRNA foci. Here, we determined composition dsRNAs. found that a subset dsRNAs originate from inverted Alu repeats...
Regional differences in the biology of colonic epithelium may determine extent involvement by ulcerative colitis. Novel monoclonal antibodies (MAbs) were used this study to investigate regional heterogeneity mucosa.MAbs generated using a method tolerisation against common antigens proximal colon and distal for immunoperoxidase staining, comparative histochemistry, immunoblotting, slot-blot analysis.The specific MAbs 5F1 (IgG3) 6G4 (IgM) stained goblet cell contents throughout normal but...
Mitosis entails complex chromatin changes that have garnered increasing interest from biologists who study genome structure and regulation—fields are being advanced by high-throughput sequencing (Seq) technologies. The application of these technologies to the mitotic requires large numbers highly pure cells, with minimal contamination interphase ensure accurate measurement phenomena specific mitosis. Here, we optimized a fluorescence-activated cell sorting (FACS)-based method for isolating...
ABSTRACT Nonsense variants underlie many genetic diseases. The phenotypic impact of nonsense is determined by nonsense-mediated mRNA decay (NMD), which degrades transcripts with premature termination codons (PTCs). Despite its clinical importance, the factors controlling transcript-specific and context-dependent variation in NMD activity remain poorly understood. Through analysis human datasets, we discovered that amino acid preceding PTC strongly influences activity. Notably, glycine...
Translational control is critical for cell fate transitions during development, lineage specification, and tumorigenesis. Here, we show that the transcription factor double homeobox protein 4 (DUX4), its previously characterized transcriptional program, broadly regulates translation to change cellular proteome. DUX4 a key regulator of zygotic genome activation in human embryos, whereas misexpression causes facioscapulohumeral muscular dystrophy (FSHD) associated with MHC-I suppression immune...
The CTCF-like protein, CTCFL, is a DNA-binding factor that regulates the transcriptional program of mammalian male germ cells. CTCFL consists eleven zinc fingers flanked by polypeptides unknown structure and function. We determined C-terminal fragment predominantly extended unordered content. Computational analysis predicts N-terminal segment also disordered. molecular architecture may then be similar to its paralog, CCCTC-binding factor, CTCF. speculate sequence divergence in unstructured...