Gene Regulation
Stem cell fate determination through protein O-GlcNAcylation
Embryonic and adult stem cells possess the capability of self-renewal and lineage-specific differentiation. The intricate balance between self-renewal and differentiation is governed by developmental signals and cell-type-specific gene regulatory mechanisms. A perturbed intra/extracellular environment during lineage specification could affect stem cell fate decisions resulting in pathology. Growing evidence demonstrates that metabolic pathways govern epigenetic regulation of gene expression during stem cell fate commitment through the utilization of metabolic intermediates or end products of metabolic pathways as substrates for enzymatic histone/DNA modifications.Regulation of translation by one-carbon metabolism in bacteria and eukaryotic organelles
Protein synthesis is an energetically costly cellular activity. It is therefore important that the process of mRNA translation remains in excellent synchrony with cellular metabolism and its energy reserves. Unregulated translation could lead to the production of incomplete, mistranslated, or misfolded proteins, squandering the energy needed for cellular sustenance and causing cytotoxicity. One-carbon metabolism (OCM), an integral part of cellular intermediary metabolism, produces a number of one-carbon unit intermediates (formyl, methylene, methenyl, methyl).H2S and reactive sulfur signaling at the host-bacterial pathogen interface
Bacterial pathogens that cause invasive disease in the vertebrate host must adapt to host efforts to cripple their viability. Major host insults are reactive oxygen and reactive nitrogen species as well as cellular stress induced by antibiotics. Hydrogen sulfide (H2S) is emerging as an important player in cytoprotection against these stressors, which may well be attributed to downstream more oxidized sulfur species termed reactive sulfur species (RSS). In this review, we summarize recent work that suggests that H2S/RSS impacts bacterial survival in infected cells and animals.Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness
Telomeres comprise specialized nucleic acid–protein complexes that help protect chromosome ends from DNA damage. Moreover, telomeres associate with subtelomeric regions through looping. This results in altered expression of subtelomeric genes. Recent observations further reveal telomere length–dependent gene regulation and epigenetic modifications at sites spread across the genome and distant from telomeres. This regulation is mediated through the telomere-binding protein telomeric repeat–binding factor 2 (TRF2).Oxygen battle in the gut: Hypoxia and hypoxia-inducible factors in metabolic and inflammatory responses in the intestine
The gastrointestinal tract is a highly proliferative and regenerative tissue. The intestine also harbors a large and diverse microbial population collectively called the gut microbiome (microbiota). The microbiome–intestine cross-talk includes a dynamic exchange of gaseous signaling mediators generated by bacterial and intestinal metabolisms. Moreover, the microbiome initiates and maintains the hypoxic environment of the intestine that is critical for nutrient absorption, intestinal barrier function, and innate and adaptive immune responses in the mucosal cells of the intestine.Emerging roles for R-loop structures in the management of topological stress
R-loop structures are a prevalent class of alternative non-B DNA structures that form during transcription upon invasion of the DNA template by the nascent RNA. R-loops form universally in the genomes of organisms ranging from bacteriophages, bacteria, and yeasts to plants and animals, including mammals. A growing body of work has linked these structures to both physiological and pathological processes, in particular to genome instability. The rising interest in R-loops is placing new emphasis on understanding the fundamental physicochemical forces driving their formation and stability.Allosteric control of metal-responsive transcriptional regulators in bacteria
Many transition metals are essential trace nutrients for living organisms, but they are also cytotoxic in high concentrations. Bacteria maintain the delicate balance between metal starvation and toxicity through a complex network of metal homeostasis pathways. These systems are coordinated by the activities of metal-responsive transcription factors—also known as metal-sensor proteins or metalloregulators—that are tuned to sense the bioavailability of specific metals in the cell in order to regulate the expression of genes encoding proteins that contribute to metal homeostasis.The transcription factor NKX1-2 promotes adipogenesis and may contribute to a balance between adipocyte and osteoblast differentiation
Although adipogenesis is mainly controlled by a small number of master transcription factors, including CCAAT/enhancer-binding protein family members and peroxisome proliferator-activated receptor γ (PPARγ), other transcription factors also are involved in this process. Thyroid cancer cells expressing a paired box 8 (PAX8)–PPARγ fusion oncogene trans-differentiate into adipocyte-like cells in the presence of the PPARγ ligand pioglitazone, but this trans-differentiation is inhibited by the transcription factor NK2 homeobox 1 (NKX2-1).The transcription factor ACE3 controls cellulase activities and lactose metabolism via two additional regulators in the fungus Trichoderma reesei
Fungi of the genus Trichoderma are a rich source of enzymes, such as cellulases and hemicellulases, that can degrade lignocellulosic biomass and are therefore of interest for biotechnological approaches seeking to optimize biofuel production. The essential transcription factor ACE3 is involved in cellulase production in Trichoderma reesei; however, the mechanism by which ACE3 regulates cellulase activities is unknown. Here, we discovered that the nominal ace3 sequence in the T. reesei genome available through the Joint Genome Institute is erroneously annotated.Shox2 regulates osteogenic differentiation and pattern formation during hard palate development in mice
During mammalian palatogenesis, cranial neural crest-derived mesenchymal cells undergo osteogenic differentiation and form the hard palate, which is divided into palatine process of the maxilla and the palatine. However, it remains unknown whether these bony structures originate from the same cell lineage and how the hard palate is patterned at the molecular level. Using mice, here we report that deficiency in Shox2 (short stature homeobox 2), a transcriptional regulator whose expression is restricted to the anterior palatal mesenchyme, leads to a defective palatine process of the maxilla but does not affect the palatine.Vigilin protein Vgl1 is required for heterochromatin-mediated gene silencing in Schizosaccharomyces pombe
Heterochromatin is a conserved feature of eukaryotic genomes and regulates various cellular processes, including gene silencing, chromosome segregation, and maintenance of genome stability. In the fission yeast Schizosaccharomyces pombe, heterochromatin formation involves methylation of lysine 9 in histone H3 (H3K9), which recruits Swi6/HP1 proteins to heterochromatic loci. The Swi6/HP1–H3K9me3 chromatin complex lies at the center of heterochromatic macromolecular assemblies and mediates many functions of heterochromatin by recruiting a diverse set of regulators.Differential and overlapping targets of the transcriptional regulators NRF1, NRF2, and NRF3 in human cells
The nuclear factor (erythroid 2)-like (NRF) transcription factors are a subset of cap'n'collar transcriptional regulators. They consist of three members, NRF1, NRF2, and NRF3, that regulate the expression of genes containing antioxidant-response elements (AREs) in their promoter regions. Although all NRF members regulate ARE-containing genes, each is associated with distinct roles. A comprehensive study of differential and overlapping DNA-binding and transcriptional activities of the NRFs has not yet been conducted.5-Formylcytosine-induced DNA–peptide cross-links reduce transcription efficiency, but do not cause transcription errors in human cells
5-Formylcytosine (5fC) is an endogenous epigenetic DNA mark introduced via enzymatic oxidation of 5-methyl-dC in DNA. We and others recently reported that 5fC can form reversible DNA–protein conjugates with histone proteins, likely contributing to regulation of nucleosomal organization and gene expression. The protein component of DNA–protein cross-links can be proteolytically degraded, resulting in smaller DNA–peptide cross-links. Unlike full-size DNA–protein cross-links that completely block replication and transcription, DNA–peptide cross-links can be bypassed by DNA and RNA polymerases and can potentially be repaired via the nucleotide excision repair (NER) pathway.Gα-13 induces CXC motif chemokine ligand 5 expression in prostate cancer cells by transactivating NF-κB
GNA13, the α subunit of a heterotrimeric G protein, mediates signaling through G-protein–coupled receptors (GPCRs). GNA13 is up-regulated in many solid tumors, including prostate cancer, where it contributes to tumor initiation, drug resistance, and metastasis. To better understand how GNA13 contributes to tumorigenesis and tumor progression, we compared the entire transcriptome of PC3 prostate cancer cells with those cells in which GNA13 expression had been silenced. This analysis revealed that GNA13 levels affected multiple CXC-family chemokines.Characterization of the internal translation initiation region in monoclonal antibodies expressed in Escherichia coli
Monoclonal antibodies (mAbs) represent an important platform for the development of biotherapeutic products. Most mAbs are produced in mammalian cells, but several mAbs are made in Escherichia coli, including therapeutic fragments. The NISTmAb is a well-characterized reference material made widely available to facilitate the development of both originator biologics and biosimilars. Here, when expressing NISTmAb from codon-optimized constructs in E. coli (eNISTmAb), a truncated variant of its heavy chain was observed.Glycerol induces G6pc in primary mouse hepatocytes and is the preferred substrate for gluconeogenesis both in vitro and in vivo
Gluconeogenesis (GNG) is de novo production of glucose from endogenous carbon sources. Although it is a commonly studied pathway, particularly in disease, there is a lack of consensus about substrate preference. Moreover, primary hepatocytes are the current gold standard for in vitro liver studies, but no direct comparison of substrate preference at physiological fasting concentrations has been performed. We show that mouse primary hepatocytes prefer glycerol to pyruvate/lactate in glucose production assays and 13C isotope tracing studies at the high concentrations commonly used in the literature, as well as at more relevant fasting, physiological concentrations.Trouble is coming: Signaling pathways that regulate general stress responses in bacteria
Bacteria can rapidly and reversibly respond to changing environments via complex transcriptional and post-transcriptional regulatory mechanisms. Many of these adaptations are specific, with the regulatory output tailored to the inducing signal (for instance, repairing damage to cell components or improving acquisition and use of growth-limiting nutrients). However, the general stress response, activated in bacterial cells entering stationary phase or subjected to nutrient depletion or cellular damage, is unique in that its common, broad output is induced in response to many different signals.The role of α-ketoglutarate–dependent proteins in pluripotency acquisition and maintenance
α-Ketoglutarate is an important metabolic intermediate that acts as a cofactor for several chromatin-modifying enzymes, including histone demethylases and the Tet family of enzymes that are involved in DNA demethylation. In this review, we focus on the function and genomic localization of these α-ketoglutarate–dependent enzymes in the maintenance of pluripotency during cellular reprogramming to induced pluripotent stem cells and in disruption of pluripotency during in vitro differentiation. The enzymatic function of many of these α-ketoglutarate–dependent proteins is required for pluripotency acquisition and maintenance.High-resolution studies of lysis–lysogeny decision-making in bacteriophage lambda
Cellular decision-making guides complex development such as cell differentiation and disease progression. Much of our knowledge about decision-making is derived from simple models, such as bacteriophage lambda infection, in which lambda chooses between the vegetative lytic fate and the dormant lysogenic fate. This paradigmatic system is broadly understood but lacking mechanistic details, partly due to limited resolution of past studies. Here, we discuss how modern technologies have enabled high-resolution examination of lambda decision-making to provide new insights and exciting possibilities in studying this classical system.Milestones in transcription and chromatin published in the Journal of Biological Chemistry
During Herbert Tabor's tenure as Editor-in-Chief from 1971 to 2010, JBC has published many seminal papers in the fields of chromatin structure, epigenetics, and regulation of transcription in eukaryotes. As of this writing, more than 21,000 studies on gene transcription at the molecular level have been published in JBC since 1971. This brief review will attempt to highlight some of these ground-breaking discoveries and show how early studies published in JBC have influenced current research. Papers published in the Journal have reported the initial discovery of multiple forms of RNA polymerase in eukaryotes, identification and purification of essential components of the transcription machinery, and identification and mechanistic characterization of various transcriptional activators and repressors and include studies on chromatin structure and post-translational modifications of the histone proteins.Computational approaches for the analysis of RNA–protein interactions: A primer for biologists
RNA-binding proteins (RBPs) play important roles in the control of gene expression and the coordination of different layers of post-transcriptional regulation. Interactions between certain RBPs and mRNA transcripts are notoriously difficult to predict, as any given protein–RNA interaction may rely not only on RNA sequence, but also on three-dimensional RNA structures, competitive inhibition from other RBPs, and input from cellular signaling pathways. Advanced and high-throughput technologies for the identification of RNA–protein interactions have come to the rescue, but the identification of binding sites and downstream functional effects of RBPs from the resulting data can be challenging.The antizyme family for regulating polyamines
The polyamines spermidine, spermine, and their precursor putrescine are organic polycations involved in various cellular processes and are absolutely essential for cellular proliferation. Because of their crucial function in the cell, their intracellular concentration must be maintained at optimal levels. To a large extent, this regulation is achieved through the activity of an autoregulatory loop that involves two proteins, antizyme (Az) and antizyme inhibitor (AzI), that regulate the first enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC), and polyamine uptake activity in response to intracellular polyamine levels.Introduction to the Thematic Minireview Series: Sixty plus years of polyamine research
Polyamines have a long history in biochemistry and physiology, dating back to 1678 when Leeuwenhoek first reported crystals that were composed of spermine phosphate in seminal fluid. Their quantification and biosynthetic pathway were first described by Herb and Celia Tabor in collaboration with Sanford Rosenthal in the late 1950s. This work led to immense interest in their physiological functions. The 11 Minireviews in this collection illustrate many of the wide-ranging biochemical effects of the polyamines.Pioneer transcription factors shape the epigenetic landscape
Pioneer transcription factors have the unique and important role of unmasking chromatin domains during development to allow the implementation of new cellular programs. Compared with those of other transcription factors, this activity implies that pioneer factors can recognize their target DNA sequences in so-called compacted or “closed” heterochromatin and can trigger remodeling of the adjoining chromatin landscape to provide accessibility to nonpioneer transcription factors. Recent studies identified several steps of pioneer action, namely rapid but weak initial binding to heterochromatin and stabilization of binding followed by chromatin opening and loss of cytosine-phosphate-guanine (CpG) methylation that provides epigenetic memory.Not just heads and tails: The complexity of the sperm epigenome
Transgenerational inheritance requires mechanisms by which epigenetic information is transferred via gametes. Canonical thought holds that mammalian sperm chromatin would be incapable of carrying epigenetic information as post-translational modifications of histones because of their replacement with protamine proteins. Furthermore, compaction of the sperm genome would hinder DNA accessibility of proteins involved in transcriptional regulation and genome architecture. In this Minireview, we delineate the paternal chromatin remodeling events during spermatogenesis and fertilization.
