These files include source datasets for the article "Multipartite stabilization of the C. beijerincki pfl ZTP aptamer disfavors terminator hairpin folding by gating strand invasion". RELATED ARTICLE: Strobel, E.J., Cheng, L., Berman, K.E. et al. A ligand-gated strand displacement mechanism for ZTP riboswitch transcription control. Nat Chem Biol 15, 1067–1076...
Prostate cancer (PCa) is the most common non-cutaneous cancer among U.S. men. Lack of effective treatments for advanced disease make it a significant public health concern. However, PCa’s long natural history makes it an excellent target for prevention approaches that reduce overtreatment of indolent disease, treatment related morbidity, and mortality....
NSD2, a histone methyltransferase specific for methylation of histone 3 lysine 36 (H3K36), exhibits a glutamic acid to lysine mutation at residue 1099 (E1099K) in childhood acute lymphocytic leukemia (ALL). Cells harboring this mutation can become the predominant clone in relapsing disease. We studied the effects of this mutant enzyme...
Transcription is tightly regulated to ensure genes are appropriately expressed both temporally and spatially. This tight regulation governs various processes within the cell, such as differentiation and cell identity, cellular maintenance, and dynamic responses to external signals. Transcription factors (TFs) coordinate these various gene programs and in particular, are key...
Oocyte meiosis is a specialized, but error prone, form of cell division that is poorly understood. Errors during meiosis often result in aneuploidy, or abnormal chromosome number, that impacts human health and fertility. Aneuploidy is the leading cause of miscarriages and birth defects, such as Down's syndrome in which cells...
Type I interferon (IFN) is the primary antiviral cytokine establishing a broad and potent antiviral response to protect mammalian cells from virus infection. The functional repertoire of IFN extends to innate and adaptive immunity, neoplastic transformation, resistance and cancer immunotherapy. IFN functions are primarily mediated through the Janus kinase (JAK)...
The cellular innate immune response to viruses is a defense mechanism executed by most cells in the human body to form the initial barrier to virus replication. Detection of viral nucleic acids initiates widespread gene expression changes that combine to establish an antiviral state and stimulate professional immune cell activation....
Proper size control of organs and tissues is critical to their function, and it is necessary for the millions of precisely sized tubes that make up those organs— for example, excessive cell growth can lead to devastating diseases such as Polycystic Kidney Disease. The regulation of tube growth is therefore...
Neural crest cells are a population of multipotent stem cells that are unique to vertebrates and give rise to a wide range of derivatives in the developing embryo, including elements of the craniofacial skeleton, pigmentation of the skin and peripheral nervous system. Although these cells reside in the ectoderm, they...
Splicing factor 3B1 (SF3B1) is a core splicing protein that stabilizes the interaction between the U2 snRNA and the branch point (BP) in the RNA target during splicing. SF3B1 is heavily phosphorylated at its N terminus and a substrate of cyclin-dependent kinases (CDKs). Although SF3B1 phosphorylation coincides with splicing catalysis,...
Many transcription factors (TFs) regulate oncogenic processes and are therefore desirable targets for drug intervention. However, few TF inhibitors have been developed to date due to a lack of specificity and few TF binding pockets. The Meade Lab has overcome these challenges by using cobalt-based complexes that disrupt Cys2His2 zinc...
Epigenetics is the study of chromatin-based events that regulate gene expression without the change of DNA sequence, including DNA methylation, histone modification and chromatin remodeling. Epigenetic regulators are encoded to modify chromatin in a highly regulated and dynamic manner. A growing number of studies have suggested the dysregulation of epigenetic...
RNA repair pathways exist in all three domains of life. In eukaryotes, they play key roles in fundamental biological processes such as tRNA splicing and endoplasmic reticulum (ER) stress induced noncanonical splicing of a master transcription factor mRNA (named XBP1 in mammalian cells). Even though most living organisms contain an...
The apolipoprotein E (APOE) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). While APOE is predominantly expressed by astrocytes in the central nervous system, neuronal expression of APOE is of increasing interest in age-related cognitive impairment, neurological injury, and neurodegeneration. Here we show that endogenous...
The blueprint of life is contained within the sequence of an organism’s genome. While virtually all cells of an individual multicellular eukaryotic organism contain a near identical code of nucleic acid sequences, an organism must give rise to and maintain a varied set of cells and phenotypes. As such, sequence...
Promyelocytic leukemia (PML) nuclear bodies act as quality control centers in the nucleus, participating in a plethora of nuclear functions. As such, PML bodies are a signature model for functional nuclear organization. PML bodies have a dynamic protein composition that responds to changing conditions of the cell. Many of the...
The literature has established glucokinase (GCK) to be the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. We have recently proposed Hexokinase Domain Containing-1 (HKDC1) to be a novel 5th HK with expression in the liver. Here, we reveal HKDC1...
Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two devastating neurodegenerative diseases that affect 100,000s of people globally. They have a severe adverse impact on society, yet there are currently no early diagnostic tools or disease-modifying therapies available. Despite their clinical heterogeneity, evidence points to these diseases being on...
Many human diseases are chronic and ultimately fatal because they damage organs and tissues beyond the body’s normal repair mechanisms. Therefore, there is significant medical interest in developing pharmaceuticals that enhance the body’s natural injury repair mechanisms and engineering organs in the lab for transplantation. However, comparatively little is known...
Contactin associated protein like 2 (CNTNAP2) has emerged as a prominent susceptibility gene implicated in multiple complex neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability (ID), and schizophrenia (SCZ). The presence of seizure comorbidity in many of these cases, as well as inhibitory neuron dysfunction in Cntnap2 knockout (KO)...
Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated Cas proteins provide an immune-like response in many prokaryotes against extraneous nucleic acids. CRISPR-Cas systems are classified into different classes and types that vary widely in composition, target recognition, and overall mechanism. The main division of CRISPR-Cas systems occurs between...
Animals must establish the correct form during development. Regeneration is a process by which some animals reestablish their form following injury. This process requires both the generation of new missing cells after injury, and information to pattern new cells to reestablish the correct form. Planarian flatworms have an almost unlimited...
The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is implicated in active transcription. Here we show that DOT1L is overexpressed in Prostate cancer (PCa) and is associated with poor clinical outcome. Genetic and chemical inhibition of DOT1L selectively impaired viability of androgen receptor (AR)-signaling competent PCa...
Skeletal muscle is one of the most abundant tissues in the body and makes up over 40% of the total body mass. It is important for mobility and posture maintenance as well as plays a central role in whole body metabolism. Skeletal muscle is made up of bundles of muscle...
Periodic exposure to light and dark as a result of rotation of the Earth have served as a major evolutionary pressure to partition divergent biological processes to different phases of the day. Mammals display periods of activity/inactivity, wake/sleep, and feeding/fasting during distinct portions of the day. In mammals, these activities...
Uterine leiomyomas (fibroids) are a major source of gynaecologic morbidity in reproductive age women and are characterised by the excessive deposition of a disorganised extracellular matrix, resulting in rigid benign tumours. Clinically, leiomyoma patients usually present with pelvic pain, urinary incontinence, as well as heavy cyclic and non-cyclic bleeding. Curative...
Background: Glioblastoma (GBM) tumors are the most malignant brain cancers and are characterized as Grade IV astrocytomas by the World Health Organization. GBM tumors can be classified into three molecular subtypes known as proneural, classical, and mesenchymal. In addition, GBM tumors also have a small population of cells known as...
When properly regulated, inflammation leads to the recruitment and activation of circulating leukocytes to maintain and restore tissue homeostasis. Although this process is critical for successful wound healing and the elimination of pathogens and infections, misdirected inflammation can exacerbate pathology and cause substantial morbidity and mortality. Inflammation a fundamental process...
The insulin/Insulin-Like Growth Factor (IGF) pathway is essential for linking nutritional status to growth and metabolism. MicroRNAs (miRNAs) are short RNAs that are players in the regulation of this process. The miRNA miR-7 shows highly conserved expression in insulin-producing cells across the animal kingdom. However, its conserved functions in regulation...
The evolutionarily conserved COMPASS family of methyltransferases implements histone H3 lysine 4 (H3K4) methylation, an epigenetic mark associated with transcriptional activation. Given the high mutational prevalence of COMPASS subunits across cancers and neurodevelopmental disorders, understanding COMPASS function would lend important insights into disease pathogenesis to facilitate development of effective therapies....
Uterine leiomyomas (fibroids) are a major source of gynaecologic morbidity in reproductive age women and are characterised by the excessive deposition of a disorganised extracellular matrix, resulting in rigid benign tumours. Clinically, leiomyoma patients usually present with pelvic pain, urinary incontinence, as well as heavy cyclic and non-cyclic bleeding. Curative...
Although centrosomes nucleate and organize microtubules in mitotically-dividing cells, spindles in female reproductive cells (oocytes) form in their absence. In some organisms acentrosomal spindle assembly is mediated by acentriolar microtubule organizing centers (MTOCs) that are thought to functionally replace centrosomes. However, spindle assembly in human oocytes does not require MTOCs;...
Heart failure due to genetic cardiomyopathy is associated with a range of phenotypic expression. The studies in this body of work interrogated the role of noncoding variation in modifying cardiomyopathy phenotypes. We used cap analysis of gene expression in heathy and failed left ventricles to define the regulatory environment of...
This dissertation focuses on the development of quantitative approaches for characterizing endogenous signaling pathways and designing new pathways in mammalian cells. I demonstrate how mathematical descriptions that are formulated to explain gene expression patterns can also serve as a powerful springboard for deeper analyses into the properties and functions of...
Proper partitioning of mitochondria and mtDNA is critical for cellular health. Investigations into mitochondrial inheritance, specifically how mtDNA inheritance is coupled with the inheritance mitochondrial compartment, are still in the early stages. We use budding yeast as a model polarized cell system to study a mitochondrial Myo2-adaptor protein, Mmr1, in...
Bacteria often coordinate virulence factors to fine-tune the host response during infection. These coordinated events can include toxins counteracting or amplifying effects of another toxin or though regulating the stability of virulence factors to remove their function once it is no longer needed. Multifunctional autoprocessing repeats-in toxin (MARTX) toxins are...
Transcription of nucleic acids (DNA and RNA) is a hallmark of life, taking the information stored within genomic nucleic acids and converting it into a form that is useful for producing the proteins necessary for cellular and organismal function. In eukaryotes, transcription of DNA into messenger RNA (mRNA) requires the...
Regulatory RNAs are found throughout nature controlling critical cellular processes and enabling cells to sense and respond to their environment. In order to provide genetic regulation, these RNAs can selectively bind to target molecules, proteins, and invading pathogens, all while modulating gene expression on both the transcriptional and translational level....
Prions are self-perpetuating, alternative protein conformations associated with neurological diseases and normal cellular functions. Saccharomyces cerevisiae contains many endogenous prions – providing a powerful system to study prionization. Previously, the Li Lab demonstrated that Swi1, a component of the SWI/SNF chromatin-remodeling complex, can form the prion [SWI+]. A small region,...
Parasitic nematode infections are common in both humans and livestock populations around the globe. In humans, these infections cause illness which can be debilitating. In livestock, parasitic nematode infections result in poor animal health and wellbeing as well as decreases in the yield of these animals. The decrease in yield...
The treatment of AML remains to be a challenge due to the high rates of resistance and relapse experienced by patients after initial therapy. The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for AML due to their critical role in malignant hematopoietic transformation via...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by motor neuron (MN) degeneration and resulting in progressive paralysis and death. ALS is genetically heterogeneous, disease pathophysiology is not completely understood, and there are no effective drug therapies. To develop broadly applicable therapeutics, we examine disease mechanisms in the...
Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. We used super-resolution and live-cell microscopy in human iPSC-derived neurons to demonstrate that mitochondria-lysosome contacts can dynamically form in the soma, axons, and dendrites of human neurons,...
Symbiotic relationships involve a life-long interaction between host and bacteria, and there is much we do not understand about how these interactions are developed and maintained. During the horizontal recruitment of beneficial bacteria by hosts, a complex set of molecular signals and communication ensures specificity. On the bacterial side, these...
Cytokines made by macrophages play a critical role in determining the course of Legionella pneumophila infection. Prior, murine-based modeling indicated that the cytokine response initiated upon recognition of L. pneumophila involves a subset of Toll-like receptors, namely TLR2, TLR5, and TLR9. Using shRNA/siRNA knockdowns and subsequently CRISPR/Cas9 knockouts (KO), I...
In nearly all Eukaryotes, the membrane-enclosed nucleus contains the vast majority of the cellular genome. Within this sub-cellular compartment, the nuclear architecture facilitates genomic chromatin organization. Controlling chromosomal loci’s spatial positioning relative to subnuclear structures and each other can have local and global effects on gene expression. Moreover, chromatin organization...
The purpose of my thesis research has been to understand the formation of mitotic chromosome structure by using chromosome micromanipulation. Folding mitotic chromosomes from their loose interphase form into their individualized, compacted form is required for easy handling of the chromosomes for cell division. This process is facilitated by several...
Protein homeostasis, or proteostasis, is essential for preserving all cellular functions and involves a balance of protein synthesis, folding, trafficking, and degradation. A collapse in proteostasis is a common feature of many neurodegenerative disorders that are characterized by the accumulation of insoluble protein aggregates in the brain. Parkinson’s disease (PD)...
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy regimens show high response rates but have debilitating effects and carry risk of relapse. Until now, no targeted therapy has been approved. In addition, 40% of patients will relapse and their treatment options are limited because...
Ensuring adequate water quality is essential for human health and for effective allocation of resources in agriculture, energy, and manufacturing. However, the current state-of-the-art for water quality testing requires expensive equipment and technical expertise to analyze samples and takes days to obtain results from off-site labs, making it inaccessible to...