The control of gene expression is regulated in a highly organized fashion to ensure specific genes are expressed at the appropriate times and levels in response to various genetic and environmental stimuli. In eukaryotes, gene expression is controlled at multiple levels from transcription factor-mediated recruitment of the basal transcription machinery at specific gene promoters to processing and maturation of the RNA transcript. Disruption of these events in humans contributes to many pathologies including cancer, metabolic syndromes, and developmental disorders. Faculty who are investigating the regulation of gene expression are interested in numerous topics including transcriptional regulatory pathways in pro- and eukaryotes, DNA and RNA interactions with proteins, RNA processing and the functions of catalytic RNA, chromatin modification and remodeling, and three-dimensional organization of genes in the nucleus. Research employs a variety of model organisms and utilizes an array of modern techniques in biochemistry and molecular, cellular, and structural biology to elucidate the mechanisms that govern gene expression in pro- and eukaryotes.
Regulation of eukaryotic gene expression through the modulation of chromatin structure and the connection to developmental disorders and cancer.
Using a combination of biochemical, cellular and genetic analyses, we would like to: analyze the structure, function and regulation of MLL complex; study the cross-talks between MLL and other histone modifying activities such as histone acetyltransferase and histone ubiquitinase; elucidate the mechanism of MLL deregulation (deletion, amplification and translocation) in leukemogenesis.
Control of gene expression in osteoblasts; regulation of bone formation.
Transcriptional regulation in bacteria is dominated by the interactions of DNA, transcription factors, and RNA polymerase sigma factors. Complexities abound, as each DNA-binding protein will have a particular spectrum of affinities for different DNA sequences, plus its own effects on the local structure of bound DNA that will in turn influence the interactions of proteins with adjacent sections of the genome.
Activity-dependent gene expression in skeletal muscle; Optic nerve regeneration; Retina regeneration.
Regulation of messenger RNA stability, translation, and localization by untranslated regions, RNA binding proteins, and nucleases.
Regulation of gene expression by proto-oncogene transcription factors; protein interactions in living cells and organisms; and nucleoprotein complex architecture.
The mechanism of post-translational modifications, such as phosphorylation and acetylation, regulating pro-apoptotic proteins in cancer cells.
Reconstitution of signal transduction systems from purified components, structure/function analysis of signal transduction enzymes, protein crystallography. Characterization of protein kinases, phosphatases, and nucleotide transferases involved in signal transduction. Organization of the gene cascade controlling nitrogen assimilation in bacteria. Development of synthetic systems that perform useful functions.
Microbial metabolism of energy-relevant and greenhouse gases (CO, CO2, methane) and xenobiotics (e.g., PCBs); regulation by and metabolism of CO in humans; and the roles of metal ions in biology, including the mechanisms of nickel, B12 , heme, and iron-sulfur enzymes. We use transient and steady-state kinetics, spectroscopy, and molecular biology to uncover mechanistic information.
Multinuclear NMR spectroscopy and imaging of intact biological systems, with an emphasis in experimental neuro-oncology, oxidative stress, and gene therapy.
Regulation of key mediators of the mammalian stress response- Corticotropin-Releasing Hormone (CRH), CRH receptors and binding protein, and corticosteroid receptors; dysregulation of the stress response in depression and anxiety-disorders.
Chemical and structural biology of enzymes that covalently modify histones, transcription factors, and other nuclear proteins. Our current research focuses on elucidating the molecular mechanisms underlying the specificites of histone methyltransferases and demethylases and on developing new assays and reagents to characterize these enzymes.
Transcriptional and post-transcriptional mechanisms that control neuronal differentiation; regulation of gene expression in the mammalian retina by microRNAs and other small RNAs.
Regulation and specificity of serine-threonine protein kinase structures; regulation of calcium channels and neurotransmitter secretion; function and regulation of neuronal activity; Cyclic nucleotides and phosphorylation in neuronal plasticity.
Biochemical and molecular studies of oncogenes and signaling pathways.
mechanistic structure-function relationships in these ncRNAs using single molecule tools and then utilize them for biomedical, bioanalytical and nanotechnological applications. The ncRNAs we study range from small RNA enzymes, such as the hammerhead, hairpin and hepatitis delta virus ribozymes with potential use in human gene therapy and relevance to human disease, to large RNA-protein complexes, such as RNA interference machinery involved in gene regulation and virus suppression.