John A Hanover

John A Hanover
National Institutes of Health | NIH · Laboratory of Cellular and Molecular Biology

Ph. D.

About

290
Publications
65,513
Reads
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18,955
Citations
Citations since 2016
63 Research Items
8619 Citations
201620172018201920202021202202004006008001,0001,2001,400
201620172018201920202021202202004006008001,0001,2001,400
201620172018201920202021202202004006008001,0001,2001,400
201620172018201920202021202202004006008001,0001,2001,400
Introduction
Our efforts are focused on understanding how nutritional and environmental factors influence epigenetic phenomena. The nutrient-driven O-GlcNAc modfication of nuclear pores and transcriptional complexes is a long term interest of the laboratory.
Additional affiliations
April 1984 - present
The National Institute of Diabetes and Digestive and Kidney Diseases
Position
  • Laboratory Chief
August 1981 - March 1984
National Cancer Institute (USA)
Position
  • PostDoc Position
April 1976 - April 1981
Johns Hopkins University
Position
  • PhD Student

Publications

Publications (290)
Article
Full-text available
Unlike the complex glycans decorating the cell surface, the O-linked β-N-acetyl glucosamine (O-GlcNAc) modification is a simple intracellular Ser/Thr-linked monosaccharide that is important for disease-relevant signaling and enzyme regulation. O-GlcNAcylation requires uridine diphosphate-GlcNAc, a precursor responsive to nutrient status and other e...
Article
Full-text available
O-GlcNAcylation is an abundant nutrient-driven modification linked to cellular signaling and regulation of gene expression. Utilizing precursors derived from metabolic flux, O-GlcNAc functions as a homeostatic regulator. The enzymes of O-GlcNAc cycling, OGT and O-GlcNAcase, act in mitochondria, the cytoplasm, and the nucleus in association with epi...
Article
Full-text available
O-GlcNAcylation is an abundant posttranslational modification in the brain implicated in human neurodegenerative diseases. We have exploited viable null alleles of the enzymes of O-GlcNAc cycling to examine the role of O-GlcNAcylation in well-characterized Caenorhabditis elegans models of neurodegenerative proteotoxicity. O-GlcNAc cycling dramatica...
Article
O-GlcNAcylation, which is a nutrient-sensitive sugar modification, participates in the epigenetic regulation of gene expression. The enzymes involved in O-linked β-D-N-acetylglucosamine (O-GlcNAc) cycling - O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) - target key transcriptional and epigenetic regulators including RNA polymerase II, histones,...
Article
Full-text available
Nutrient-driven O-GlcNAcylation of key components of the transcription machinery may epigenetically modulate gene expression in metazoans. The global effects of GlcNAcylation on transcription can be addressed directly in C. elegans because knockouts of the O-GlcNAc cycling enzymes are viable and fertile. Using anti-O-GlcNAc ChIP-on-chip whole-genom...
Article
Full-text available
Fabry disease is an X-linked glycolipid storage disorder caused by mutations in the GLA gene which result in a deficiency in the lysosomal enzyme alpha galactosidase A (AGA). As a result, the glycolipid substrate Gb3 accumulates in critical tissues and organs producing a progressive debilitating disease. In Fabry disease up to 80% of patients exper...
Article
Full-text available
Animal behavior is influenced by the competing drives to maintain energy and to reproduce. The balance between these evolutionary pressures and how nutrient signaling pathways intersect with mating remains unclear. The nutrient sensor O- GlcNAc transferase, which post-translationally modifies intracellular proteins with a single monosaccharide, is...
Article
How ancestry-associated genetic variance affects disparities in the risk for polygenic diseases and influences the identification of disease-associated genes warrant a deeper understanding. We hypothesized that the discovery of genes associated with polygenic diseases may be limited by overreliance on single-nucleotide polymorphism (SNP)-based geno...
Article
Full-text available
Protein O-GlcNAcylation is a nutrient and stress-sensitive protein post-translational modification (PTM). The addition of an O-GlcNAc molecule to proteins is catalyzed by O-GlcNAc transferase (OGT), whereas O-GlcNAcase (OGA) enzyme is responsible for removal of this PTM. Previous work showed that OGT is highly expressed in the pancreas, and we demo...
Article
Full-text available
Genetic and environmental manipulations, such as dietary restriction, can improve both health span and lifespan in a wide range of organisms, including humans. Changes in nutrient intake trigger often overlapping metabolic pathways that can generate distinct or even opposite outputs depending on several factors, such as when dietary restriction occ...
Article
Full-text available
Although traditionally considered a glucose metabolism-associated modification, the O -linked β-N-Acetylglucosamine ( O- GlcNAc) regulatory system interacts extensively with lipids and is required to maintain lipid homeostasis. The enzymes of O- GlcNAc cycling have molecular properties consistent with those expected of broad-spectrum environmental...
Article
Full-text available
Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the lysosomal enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). As a result, the glycolipid substrate, globotriaosylceramide (Gb3) accumulates in various cell types throughout the body producing a multisystem disease that affects the vascular, cardiac, re...
Article
Full-text available
Carbohydrates involving glycoconjugates play a pivotal role in many life processes. Better understanding toward glycobiological events including the structure–function relationship of these biomolecules and for diagnostic and therapeutic purposes including tailor-made vaccine development and synthesis of structurally well-defined oligosaccharides (...
Preprint
Full-text available
Animal behavior is influenced by the competing drives to maintain energy and to reproduce. The balance between these evolutionary pressures and how nutrient signaling pathways intersect with mating drive remains unclear. The nutrient sensor O -GlcNAc transferase, which post-translationally modifies intracellular proteins with a single monosaccharid...
Article
The O-GlcNAc post-translational modification is reversibly added onto intracellular proteins. It is a unique glucose rheostat for cell signaling relying on the availability of UDP-GlcNAc, itself reflecting extracellular glucose. With more than 7000 human targets identified to date, O-GlcNAcylation regulates numerous physiological processes such as...
Article
Full-text available
Inflammation is the immune response to harmful stimuli, including pathogens, damaged cells and toxic compounds. However, uncontrolled inflammation can be detrimental and contribute to numerous chronic inflammatory diseases, such as insulin resistance. At the forefront of this response are macrophages, which sense the local microenvironment to respo...
Article
Full-text available
Tissue homeostasis requires a delicate balance between stem cell self-renewal, proliferation, and differentiation. Essential to this process is glycosylation, with both intra-and extra-cellular glycosylation being required for stem cell homeostasis. However, it remains unknown how intracellular glycosylation, O-GlcNAcylation, interfaces with cellul...
Article
Galectin-3 is a chimeric galectin involved in diverse intracellular and extracellular functions. Galectin-3 is synthesized in the cytoplasm and then released extracellularly by a poorly understood non-canonical secretion mechanism. As a result, it can play important roles both inside and outside the cell. One important extracellular role of galecti...
Article
Full-text available
Endomembrane glycosylation and cytoplasmic O-GlcNAcylation each play essential roles in nutrient sensing, and characteristic changes in glycan patterns have been described in disease states such as diabetes and cancer. These changes in glycosylation have important functional roles and can drive disease progression. However, little is known about th...
Article
Full-text available
Background and Aims The liver has a unique capacity to regenerate after injury in a highly orchestrated and regulated manner. Here we report that O-GlcNAcylation, an intracellular post-translational modification (PTM) regulated by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a critical termination signal for liver regeneration...
Article
The vast array of cell types of multicellular organisms must individually fine-tune their internal metabolism. One important metabolic and stress regulatory mechanism is the dynamic attachment/removal of glucose-derived sugar N-acetylglucosamine on proteins (O-GlcNAcylation). The number of proteins modified by O-GlcNAc is bewildering, with at least...
Article
Full-text available
O -GlcNAcylation is a prevalent form of glycosylation that regulates proteins within the cytosol, nucleus, and mitochondria. The O -GlcNAc modification can affect protein cellular localization, function, and signaling interactions. The specific impact of O -GlcNAcylation on mitochondrial morphology and function has been elusive. In this manuscript,...
Preprint
Full-text available
The liver has a unique capacity to regenerate after injury in a highly orchestrated and regulated manner. Here we report that O-GlcNAcylation, an intracellular post-translational modification (PTM) regulated by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a critical termination signal for liver regeneration (LR) following parti...
Article
Full-text available
Caloric need has long been thought a major driver of appetite. However, it is unclear whether caloric need regulates appetite in environments offered by many societies today where there is no shortage of food. Here we observed that wildtype mice with free access to food did not match calorie intake to calorie expenditure. While the size of a meal a...
Article
Full-text available
The reversible posttranslational O-GlcNAc modification of serine or threonine residues of intracellular proteins is involved in many cellular events from signaling cascades to epigenetic and transcriptional regulation. O-GlcNAcylation is a conserved nutrient-dependent process involving two enzymes, with O-GlcNAc transferase (OGT) adding O-GlcNAc an...
Article
Full-text available
Glioblastoma (GBM) is a grade IV glioma highly aggressive and refractory to the therapeutic approaches currently in use. O-GlcNAcylation plays a key role for tumor aggressiveness and progression in different types of cancer; however, experimental evidence of its involvement in GBM are still lacking. Here, we show that O-GlcNAcylation plays a critic...
Article
Full-text available
Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are key regulators of metabolism. Here, we report a previously unknown function for the hepatic FXR-SHP axis in controlling protein N-linked glycosylation. Transcriptome analysis in liver-specific Fxr-Shp double knockout (LDKO) livers revealed induction of genes encodi...
Preprint
Endomembrane glycosylation and cytoplasmic O-GlcNAcylation each play essential roles in nutrient sensing, and in fact, characteristic changes in glycan patterns have been described in disease states such as diabetes and cancer. These changes in glycosylation have important functional roles and can drive disease progression. However, little is known...
Article
Full-text available
Rationale The beta-O-linkage of N-acetylglucosamine (i.e., O-GlcNAc) to proteins is a pro-adaptive response to cellular insults. To this end, increased protein O-GlcNAcylation improves short-term survival of cardiomyocytes subjected to acute injury. This observation has been repeated by multiple groups and in multiple models; however, whether incre...
Article
Full-text available
The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson’s disease and prematurely degenerate in the course of disease progression, whil...
Article
Full-text available
The conserved O-GlcNAc transferase OGT O-GlcNAcylates serine and threonine residues of intracellular proteins to regulate their function. OGT is required for viability in mammalian cells, but its specific roles in cellular physiology are poorly understood. Here we describe a conserved requirement for OGT in an essential aspect of cell physiology: t...
Preprint
Full-text available
Genetic and environmental manipulations, such as dietary restriction (DR), can improve both health span and lifespan in a wide range of organisms, including humans. Changes in nutrient intake trigger often overlapping metabolic pathways that can generate distinct or even opposite outputs depending on several factors, such as when DR occurs in the l...
Preprint
Full-text available
The conserved O -GlcNAc transferase OGT O -GlcNAcylates serine and threonine residues of intracellular proteins to regulate their function. OGT is required for viability in mammalian cells, but its specific roles in cellular physiology are poorly understood. Here we describe a conserved requirement for OGT in an essential aspect of cell physiology:...
Article
Full-text available
Stem/progenitor cells exhibit high proliferation rates, elevated nutrient uptake, altered metabolic flux, and stress-induced genome instability. O-GlcNAcylation is an essential post-translational modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which act in a nutrient- and stress-responsive manner. The precise role of O-Gl...
Article
Full-text available
Small numbers of hematopoietic stem cells (HSCs) balance self-renewal and differentiation to produce the diversity and abundance of cell types that make up the blood system. How nutrients are recruited to support this massive differentiation and proliferation process remains largely unknown. The unique metabolism of adult HSCs, which rely on glycol...
Article
Full-text available
Non-nutritive sweeteners (NNS) are marketed as sugar alternatives providing sweet taste with few or no calories. Yet their consumption has been linked to metabolic dysfunction and changes in the gut microbiome. NNS exposure mostly originates from diet beverages and sweetener packages in adults or breastmilk in infants. Consequences of early life ex...
Article
Full-text available
Accumulation of hyper-phosphorylated tau, a microtubule-associated protein, plays an important role in the progression of Alzheimer's disease (AD). Animal studies suggest that one strategy for treating AD and related tauopathies may be inhibition of O-GlcNAcase (OGA), which may subsequently decrease pathological tau phosphorylation Here, we report...
Article
Full-text available
Nutrient-driven O-GlcNAcylation has been linked to epigenetic regulation of gene expression in metazoans. In C. elegans, O-GlcNAc marks the promoters of over 800 developmental, metabolic, and stress-related genes; these O-GlcNAc marked genes show a strong 5′, promoter-proximal bias in the distribution of RNA Polymerase II (Pol II). In response to s...
Article
Full-text available
O-GlcNAcylation is an abundant post translational protein modification in which the monosaccharide β-N-acetyl-D-glucosamine (O-GlcNAc) is added to Ser/Thr residues by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA). Analyses of O-GlcNAc-mediated signaling and metabolic phenomena are complicated by factors including unsatisfactory inhibi...
Article
Full-text available
Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueledby oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glyco-sylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-Gl...
Article
O‐GlcNAcylation is an essential post‐translational modification important for integrating metabolism with cell physiology. Using diverse model systems, studies of this evolutionarily conserved intracellular glycosylation have highlighted its role in stem cell maintenance, lineage specification and disease. Although discovered over 30 years ago, the...
Article
Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueledby oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glyco-sylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-Gl...
Article
Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient sensitive nucleocytoplasmi...
Article
Full-text available
PurposeAdults with Turner syndrome (TS) have an increased predisposition to ischemic heart disease. The quantitative relationship between coronary atherosclerosis and TS has yet to be established.MethodsA total of 128 females (62 with TS) participated in this prospective study. Coronary computed tomography angiography was performed to measure coron...
Article
Full-text available
Oxidative damage contributes to human diseases of aging including diabetes, cancer, and cardiovascular disorders. Reactive oxygen species resulting from xenobiotic and endogenous metabolites are sensed by a poorly understood process, triggering a cascade of regulatory factors and leading to the activation of the transcription factor Nrf2 (SKN-1 in...
Article
The dynamic carbohydrate post-translational modification (PTM) O-linked N-acetyl glucosamine (O-GlcNAc) is found on thousands of proteins throughout the nucleus and cytoplasm, and rivals phosphorylation in terms of the number of substrates and pathways influenced. O-GlcNAc is highly conserved and essential in most organisms, with disruption of O-Gl...
Article
Full-text available
Background The discovery of disease pathogenesis requires systematic agnostic screening of multiple homeostatic processes that may become deregulated. We illustrate this principle in the evaluation and diagnosis of a 5-year-old boy with Joubert syndrome type 10 (JBTS10). He carried the OFD1 mutation p.Gln886Lysfs*2 (NM_003611.2: c.2656del) and mani...
Article
Full-text available
Nutrient-driven O-GlcNAcylation is strikingly abundant in the brain and has been linked to development and neurodegenerative disease. We selectively targeted the O-GlcNAcase (Oga) gene in the mouse brain to define the role of O-GlcNAc cycling in the central nervous system. The brain-knockout animals exhibited dramatically increased brain O-GlcNAc l...
Article
Azido-6-deoxy-N-acetylglucosamine (6AzGlcNAc) was recently introduced as a new selective metabolic chemical reporter (MCR) for labeling O-GlcNAc-modified proteins in cells. To investigate whether O-6AzGlcNAc is readily cleaved by O-GlcNAcase (OGA), the enzyme responsible for removing the O-GlcNAc modification, we synthesized PNP-6AzGlcNAc. This ana...
Article
Lectin-based flow cytometry using L-PHA provides a method to screen for PGM3 deficiency.
Article
Full-text available
Human exome sequencing has dramatically increased the rate of identification of disease-associated polymorphisms. However, examining the functional consequences of those variants has created an analytic bottleneck. Insulin-like signaling in $\textit{Caenorhabditis elegans}$ has long provided a model to assess consequences of human insulin signaling...
Article
Full-text available
Human exome sequencing has dramatically increased the rate of identification of disease-associated polymorphisms. However, examining the functional consequences of those variants has created an analytic bottleneck. Insulin-like signaling in Caenorhabditis elegans has long provided a model to assess consequences of human insulin signaling mutations,...
Article
Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). It is a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. One of the hallmarks of this disorder is neuropathic pain and sympathetic and parasympathetic nervous dysfunc...
Article
Full-text available
The genetically amenable mouse model has led to a large collection of genetically defined lines from which mouse embryonic fibroblasts (MEFs) have been derived. Despite their widespread use, MEFs are time consuming to generate and have a limited lifespan. Immortalizing primary MEFs with the desired genetic manipulations greatly reduces culture main...
Article
Full-text available
Gene expression during Drosophila development is subject to regulation by the Polycomb (Pc), Trithorax (Trx) and Compass chromatin modifier complexes. O-GlcNAc Transferase (OGT/SXC) is essential for Pc repression suggesting that the O-GlcNAcylation of proteins plays a key role in regulating development. OGT transfers O-GlcNAc onto serine and threon...
Article
Full-text available
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring au...