A5003435130- CRISPR and Genetic Engineering
- RNA Research and Splicing
- RNA modifications and cancer
- Cancer, Hypoxia, and Metabolism
- TGF-β signaling in diseases
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Genetics, Aging, and Longevity in Model Organisms
- Kruppel-like factors research
- MicroRNA in disease regulation
- Microbial Natural Products and Biosynthesis
- Lung Cancer Research Studies
- Growth Hormone and Insulin-like Growth Factors
- Cancer Research and Treatments
- Advanced Breast Cancer Therapies
- Biochemical and Molecular Research
- Chromosomal and Genetic Variations
- Mitochondrial Function and Pathology
- Ferroptosis and cancer prognosis
- Ion Channels and Receptors
- Bladder and Urothelial Cancer Treatments
- Genetic Syndromes and Imprinting
- Calcium signaling and nucleotide metabolism
- RNA and protein synthesis mechanisms
- Nanoplatforms for cancer theranostics
The University of Texas Southwestern Medical Center
2019-2024
Children's Medical Center
2021
University of Michigan
2010-2015
Michigan United
2012-2013
Population Council
2007-2008
McGill University
2007
Rockefeller University
2007
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,...
Three-prime untranslated regions (3'UTRs) of metazoan messenger RNAs (mRNAs) contain numerous regulatory elements, yet remain largely uncharacterized. Using polyA capture, 3' rapid amplification complementary DNA (cDNA) ends, full-length cDNAs, and RNA-seq, we defined approximately 26,000 distinct 3'UTRs in Caenorhabditis elegans for 85% the 18,328 experimentally supported protein-coding genes revised 40% gene models. Alternative 3'UTR isoforms are frequent, often differentially expressed...
Small RNAs regulate diverse biological processes by directing effector proteins called Argonautes to silence complementary mRNAs. Maturation of some classes small involves terminal 2'-O-methylation prevent degradation. This modification is catalyzed members the conserved HEN1 RNA methyltransferase family. In animals, Piwi-interacting (piRNAs) and endogenous exogenous interfering (siRNAs) are methylated, whereas microRNAs not. However, mechanisms that determine animal substrate specificity...
Significance Melanoma metastasis is limited by oxidative stress. Cells that enter the blood experience high levels of reactive oxygen species and usually die ferroptosis. We found melanoma cells become more dependent upon pentose phosphate pathway to manage stress during metastasis. When function was impaired reduced glucose 6-phosphate dehydrogenase ( G6PD ) function, increased malic enzyme activity glutamine consumption. thus have redundant layered protection against
We screen ion channels and transporters throughout the genome to identify those required by human melanoma cells but not normal melanocytes. discover that Mucolipin-1 (MCOLN1), which encodes lysosomal cation channel TRPML1, is preferentially for survival proliferation of cells. Loss MCOLN1/TRPML1 function impairs growth patient-derived melanomas in culture xenografts does affect TRPML1 expression macropinocytosis are elevated relative negatively regulate MAPK pathway mTORC1 signaling....
Piwi-interacting RNAs (piRNAs) fulfill a critical, conserved role in defending the genome against foreign genetic elements. In many organisms, piRNAs appear to be derived from processing of long, polycistronic RNA precursor. Here, we establish that each Caenorhabditis elegans piRNA represents tiny, autonomous transcriptional unit. Remarkably, minimal C. cassette requires only 21 nucleotide (nt) sequence and an ∼50 nt upstream motif with limited genomic context for expression. Combining...
Transforming growth factor β superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins inhibins, which respectively stimulate hinder Fshb subunit transcription in gonadotrope cells. More recently, members of bone morphogenetic protein (BMP) sub-family were shown to a manner analogous activins. Here, we used murine cell line, LβT2, investigate mechanisms through BMP2 regulates gene. Although expressed at low levels LβT2 cells, Bmp2 mRNA...
Paired-like homeodomain transcription factors (PITX) regulate the activity of pituitary hormone-encoding genes. Here, we examined mechanisms through which family PITX proteins control murine FSH β-subunit (Fshb) transcription. We observed that endogenous PITX1 and PITX2 isoforms from LβT2 gonadotrope cells could bind a highly conserved proximal cis-element. Transfection or PITX2C in heterologous stimulated both human Fshb/FSHB promoter-reporter activities, cases, mutation critical...
Significance MicroRNAs (miRNAs) are critical regulators of diverse biological processes. Despite rapid advances in understanding miRNA biogenesis and function, a gap remains our knowledge how effector complex activity [miRNA-induced silencing (miRISC)] is modulated. Specifically, the importance posttranslational protein modifications controlling miRISC largely unexplored. Here, we characterize previously unidentified role for conserved serine/threonine kinase, casein kinase II (CK2),...
Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small lung cancer (SCLC) cells with inherent high by blocking RxL-mediated interactions cyclin A B select substrates. Genome-wide CRISPR/Cas9 knockout random mutagenesis screens found A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically B- Cdk2-dependent spindle assembly checkpoint...
Alternative polyadenylation (APA) is widespread in neuronal development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. We used systematic genetic studies genome-wide surveys of transcriptional landscape to identify a context-dependent regulatory pathway controlling APA Caenorhabditis elegans nervous system. Loss function ssup-72 , Ser5 phosphatase for RNA polymerase II (Pol II) C-terminal domain (CTD), dampens transcription...
Orphan cytotoxins are small molecules for which the mechanism of action (MoA) is either unknown or ambiguous. Unveiling these compounds may lead to useful tools biological investigation and in some cases, new therapeutic leads. In select DNA mismatch repair-deficient colorectal cancer cell line, HCT116, has been used as a tool forward genetic screens identify compound-resistant mutations, have ultimately led target identification. To expand utility this approach, we engineered lines with...
Abstract The pentose phosphate pathway is a major source of NADPH for oxidative stress resistance in cancer cells but there limited insight into its role metastasis, when some experience high levels stress. To test this, we mutated the substrate binding site Glucose-6-phosphate dehydrogenase (G6PD), which catalyzes first step pathway, patient-derived melanomas. G6PD mutant melanomas had significantly decreased enzymatic activity and depletion intermediates branch pathway. Reduced function...
The selective synthesis and release of FSH from gonadotropes is regulated by the TGF-beta proteins, activins inhibins. Inhibins ovary antagonize local actions pituitary activins. We others have shown that directly stimulate transcription rodent porcine beta-subunit (FSHb) genes, rate-limiting step in mature hormone synthesis. Here, we hypothesized FSHb promoter sensitivity to differs between species thereby contributes species-specific patterns secretion across reproductive cycle. previously...
Abstract To study distant metastasis we developed a patient-derived xenograft (PDX) assay in which melanoma cells from patients spontaneously metastasize NOD/SCID IL2Rγnull (NSG) mice manner that correlates with metastatic behavior (Sci Transl Med 4:159). Using this assay, discovered is limited by oxidative stress (Nature 527:186). Reactive Oxygen Species (ROS) increase dramatically as they through the blood. The rare survive undergo reversible metabolic changes confer resistance. We found...