Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in Alzheimer's disease (...) (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long‐term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity‐dependent recruitment of postsynaptic AMPA‐type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory‐associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD. (shrink)

Histone acetylation is an important regulatory mechanism that controls transcription and diverse nuclear processes. While great progress has been made in understanding how localized acetylation and deacetylation control promoter activity, virtually nothing is known about the consequences of acetylation throughout entire chromosomal regions. An increasing number of genes have been found to reside in large chromatin domains that are controlled by regulatory elements many kilobases away. Recent studies have shown that broad histone acetylation patterns are hallmarks (...) of chromatin domains. The purpose of this review is to discuss how such patterns are established and their implications for regulating gene expression. BioEssays 23:820–830, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Lysine acetylation has been shown to occur in many protein targets, including core histones, about 40 transcription factors and over 30 other proteins. This modification is reversible in vivo, with its specificity and level being largely controlled by signal‐dependent association of substrates with acetyltransferases and deacetylases. Like other covalent modifications, lysine acetylation exerts its effects through “loss‐of‐function” and “gain‐of‐function” mechanisms. Among the latter, lysine acetylation generates specific docking sites for bromodomain proteins. For example, bromodomains of Gcn5, PCAF, (...) TAF1 and CBP are able to recognize acetyllysine residues in histones, HIV Tat, p53, c‐Myb or MyoD. In addition to the acetyllysine moiety, the flanking sequences also contribute to efficient recognition. The relationship between acetyllysine and bromodomains is reminiscent of the specific recognition of phosphorylated residues by phospho‐specific binding modules such as SH2 domains and 14‐3‐3 proteins. Therefore, lysine acetylation forges a novel signaling partnership with bromodomains to govern the temporal and spatial regulation of protein functions in vivo. BioEssays 26:1076–1087, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The N‐end rule denotes the relationship between the identity of the amino‐terminal residue of a protein and its in vivo half‐life. Since its discovery in 1986, the N‐end rule has generally been described by a defined set of rules for determining whether an amino‐terminal residue is stabilizing or not. However, recent studies are revealing that this N‐end rule (or N‐degron concept) is less straightforward than previously appreciated. For instance, it is unveiled that N‐terminal acetylation of N‐terminal residues may create (...) a degradation signal (Ac‐degron) that promotes the degradation of target proteins. A recent high‐throughput dissection of degrons in yeast proteins amino termini intriguingly suggested that the hydrophobicity of amino‐terminal residues—but not the N‐terminal acetylation status—may be the indispensable feature of amino‐terminal degrons. Herein, these recent advances in N‐terminal acetylation and the complexity of N‐terminal degradation signals in the context of the N‐degron pathway are analyzed. (shrink)

Immunofluorescent labelling demonstrates that human metaphase chromosomes contain hyperacetylated histone H4. With the exception of the inactive X chromosome in female cells, where the bulk of histone H4 is under‐acetylated, H4 hyperacetylation is non‐uniformly distributed along the chromosomes and clustered in cytologically resolvable chromatin domains that correspond, in general, with the R‐bands of conventional staining. The strongest immunolabelling is often found in T‐bands, the subset of intense R‐bands having the highest GC content. The majority of mapped genes also occurs in (...) R‐band regions, with the highest gene density in T‐bands. These observations are consistent with a model in which hyperacetylation of histone H4 marks the position of potentially active gene sequences on metaphase chromosomes. Since acetylation is maintained during mitosis, progeny cells receive an imprint of the histone H4 acetylation pattern that was present on the parental chromosomes before cell division. Histone acetylation could provide a mechanism for propagating cell memory, defined as the maintenance of committed states of gene expression through cell lineages. (shrink)

It is becoming clear that the post‐translational modification of histone and non‐histone proteins by acetylation is part of an important cellular signaling process controling a wide variety of functions in both the nucleus and the cytoplasm. Recent investigations designate this signaling pathway as one of the primary targets of viral proteins after infection. Indeed, specific viral proteins have acquired the capacity to interact with cellular acetyltransferases (HATs) and deacetylases (HDACs) and consequently to disrupt normal acetylation signaling pathways, thereby (...) affecting viral and cellular gene expression. Here we review the targeting of cellular HATs and HDACs by viral proteins and highlight different strategies adopted by viruses to control cellular acetylation signaling and to accomplish their life cycle. BioEssays 25:58–65, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

Reversible acetylation at the ϵ‐amino group of lysines located at the conserved domain of core histones is supposed to play an important role in the regulation of chromatin structure and its transcriptional activity. One promising strategy for analyzing the precise function of histone acetylation is to block the activities of acetylating or deacetylating enzymes by specific inhibitors. Recently, two microbial metabolites, trichostatin A and trapoxin, were found to be potent inhibitors of histone deacetylases. Trichostatin A reversibly inhibits the (...) mammalian histone deacetylase, whereas trapoxin causes inhibition through irreversible binding to the enzyme. The histone deacetylase from a trichostatin A‐resistant cell line is resistant to trichostatin A, indicating that the enzyme is the primary target. Both of the agents induce a variety of biological responses of cells such as induction of differentiation and cell cycle arrest. Trichostatin A and trapoxin are useful in analyzing the role of histone acetylation in chromatin structure and function as well as in determining the genes whose activities are regulated by histone acetylation. (shrink)

The aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. NF‐κB signaling is the master regulator of the both immune systems. Two recent articles highlight the role of the NF‐κB system in aging and immune responses. Adler et al1 showed that the NF‐κB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. Kwon et al2 studying HIV‐1 infection and subsequent immune deficiency process demonstrated that HIV‐1 Tat (...) protein binds to SIRT1 protein, a well‐known longevity factor, and inhibits the SIRT1‐mediated deacetylation of the p65 component of the NF‐κB complex. As a consequence, the transactivation efficiency of the NF‐κB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF‐κB transactivation efficiency. Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF‐κB signaling, the major outcome of which is inflamm‐aging via proinflammatory responses. BioEssays 30:939–942, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Chemiosmotic coupling − the harnessing of electrochemical ion gradients across membranes to drive metabolism − is as universally conserved as the genetic code. As argued previously in these pages, such deep conservation suggests that ion gradients arose early in evolution, and might have played a role in the origin of life. Alkaline hydrothermal vents harbour pH gradients of similar polarity and magnitude to those employed by modern cells, one of many properties that make them attractive models for life's origin. Their (...) congruence with the physiology of anaerobic autotrophs that use the acetyl CoA pathway to fix CO2 gives the alkaline vent model broad appeal to biologists. Recently, however, a paper by Baz Jackson criticized the hypothesis, concluding that natural pH gradients were unlikely to have played any role in the origin of life. Unfortunately, Jackson mainly criticized his own interpretations of the theory, not what the literature says. This counterpoint is intended to set the record straight. (shrink)

Bromodomain‐containing 4 (BRD4), a member of Bromo and Extra‐Terminal (BET) family, recognizes acetylated histones and is of importance in transcription, replication, and DNA repair. It also binds non‐histone proteins, DNA and RNA, contributing to development, tissue growth, and various physiological processes. Additionally, BRD4 has been implicated in driving diverse diseases, ranging from cancer, viral infection, inflammation to neurological disorders. Inhibiting its functions with BET inhibitors (BETis) suppresses the progression of several types of cancer, creating an impetus for translating these chemicals (...) to the clinic. The diverse roles of BRD4 are largely dependent on its interaction partners in different contexts. In this review we discuss the molecular mechanisms of BRD4 with its interacting partners in physiology and pathology. Current development of BETis is also summarized. Further understanding the functions of BRD4 and its partners will facilitate resolving the liabilities of present BETis and accelerate their clinical translation. (shrink)

Neurological diseases (NDs), featured by progressive dysfunctions of the nervous system, have become a growing burden for the aging populations. N‐Deacetylase and N‐sulfotransferase 3 (NDST3) is known to catalyze deacetylation and N‐sulfation on disaccharide substrates. Recently, NDST3 is identified as a novel deacetylase for tubulin, and its newly recognized role in modulating microtubule acetylation and lysosomal acidification provides fresh insights into ND therapeutic approaches using NDST3 as a target. Microtubule acetylation and lysosomal acidification have been reported to be (...) critical for activities in neurons, implying that the regulators of these two biological processes, such as the previously known microtubule deacetylases, histone deacetylase 6 (HDAC6) and sirtuin 2 (SIRT2), could play important roles in various NDs. Aberrant NDST3 expression or tubulin acetylation has been observed in an increasing number of NDs, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), schizophrenia and bipolar disorder, Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting that NDST3 is a key player in the pathogenesis of NDs and may serve as a target for development of new treatment of NDs. (shrink)

Histone acetylation has been recognized as an important post‐translational modification of core nucleosomal histones that changes access to the chromatin to allow gene transcription, DNA replication, and repair. Histone acetyltransferases were initially identified as co‐activators that link DNA‐binding transcription factors to the general transcriptional machinery. Over the years, more chromatin‐binding modes have been discovered suggesting direct interaction of histone acetyltransferases and their protein complex partners with histone proteins. While much progress has been made in characterizing histone acetyltransferase complexes biochemically, (...) cell‐free activity assay results are often at odds with in‐cell histone acetyltransferase activities. In‐cell studies suggest specific histone lysine targets, but broad recruitment modes, apparently not relying on specific DNA sequences, but on chromatin of a specific functional state. Here we review the evidence for general versus specific roles of individual nuclear lysine acetyltransferases in light of in vivo and in vitro data in the mammalian system. (shrink)

Amine acetylation is a diverse topic with importance to the regulation of several physiological processes as well as the metabolism of drugs and environmental chemicals. Arylalkylamine N‐acetyltransferase is widely distributed in several species, where this enzyme plays an important role in the seasonal regulation of reproduction and photoperiodism in vertebrates through the pathway of melatonin formation. In insects, this enzyme is involved in monoamine neurotransmitter inactivation and the formation of catecholamine intermediates necessary for sclerotization of the insect cuticle.

Acetylation of histones is an essential element regulating chromatin structure and transcription. MYST (Moz, Ybf2/Sas3, Sas2, Tip60) proteins form the largest family of histone acetyltransferases and are present in all eukaryotes. Surprisingly, until recently this protein family was poorly studied. However, in the last few years there has been a substantial increase in interest in the MYST proteins and a number of key studies have shown that these chromatin modifiers are required for a diverse range of cellular processes, both (...) in health and disease. Translocations affecting MYST histone acetyltransferases can lead to leukemia and solid tumors. Some members of the MYST family are required for the development and self‐renewal of stem cell populations; other members are essential for the prevention of inappropriate heterochromatin spreading and for the maintenance of adequate levels of gene expression. In this review we discuss the function of MYST proteins in vivo. (shrink)

Acetylation of internal lysine residues of core histone N-terminal domains has been found correlatively associated with transcriptional activation in eukaryotes for more than three decades. Recent discoveries showing that several transcriptional regulators possess intrinsic histone acetyltransferase (HAT) and deacetylase (HDAC) activities strongly suggest that histone acetylation and deacetylation each plays a causative role in regulating transcription. Intriguingly, several HATs have been shown an ability to acetylate nonhistone protein substrates (e.g., transcription factors) in vitro as well, suggesting the possibility (...) that internal lysine acetylation of multiple proteins exists as a rapid and reversible regulatory mechanism much like protein phosphorylation. This article reviews recent developments in histone acetylation and transcriptional regulation. We also discuss several important, yet unanswered, questions. BioEssays 20:615–626, 1998. © 1998 John Wiley & Sons Inc. (shrink)

The chromatin‐regulatory principles of histone post‐translational modifications (PTMs) are discussed with a focus on the potential alterations in chromatin functional state due to steric and mechanical constraints imposed by bulky histone modifications such as ubiquitin and SUMO. In the classical view, PTMs operate as recruitment platforms for histone “readers,” and as determinants of chromatin array compaction. Alterations of histone charges by “small” chemical modifications (e.g., acetylation, phosphorylation) could regulate nucleosome spontaneous dynamics without globally affecting nucleosome structure. These fluctuations in (...) nucleosome wrapping can be exploited by chromatin‐processing machinery. In contrast, ubiquitin and SUMO are comparable in size to histones, and it seems logical that these PTMs could conflict with canonical nucleosome organization. An experimentally testable hypothesis that by adding sterical bulk these PTMs can robustly alter nucleosome primary structure is proposed. The model presented here stresses the diversity of mechanisms by which histone PTMs regulate chromatin dynamics, primary structure and, hence, functionality. (shrink)

Recent studies have provided evidence of associations between neurochemistry and reading (dis)ability (Pugh et al., 2014). Based on a long history of studies indicating that fluent reading entails the automatic convergence of the written and spoken forms of language and our recently proposed Neural Noise Hypothesis (Hancock et al., 2017), we hypothesized that individual differences in cross-modal integration would mediate, at least partially, the relationship between neurochemical concentrations and reading. Cross-modal integration was measured in 231 children using a two-alternative forced (...) choice cross-modal matching task with three language conditions (letters, words, and pseudowords) and two levels of difficulty within each language condition. Neurometabolite concentrations of Choline (Cho), Glutamate (Glu), gamma-Aminobutyric (GABA), and N- acetyl-aspartate (NAA) were then measured in a subset of this sample (n = 70) with Magnetic Resonance Spectroscopy (MRS). A structural equation mediation model revealed that the effect of cross-modal word matching mediated the relationship between increased Glu (which has been proposed to be an index of neural noise) and poorer reading ability. In addition, the effect of cross-modal word matching fully mediated a relationship between increased Cho and poorer reading ability. Multilevel mixed effects models confirmed that lower Cho predicted faster cross-modal matching reaction time, specifically in the hard word condition. These Cho... (shrink)

The ring‐shaped ATPase machine, cohesin, regulates sister chromatid cohesion, transcription, and DNA repair by topologically entrapping DNA. Here, we propose a rigid scaffold model to explain how the cohesin regulators Pds5 and Wapl release cohesin from chromosomes. Recent studies have established the Smc3‐Scc1 interface as the DNA exit gate of cohesin, revealed a requirement for ATP hydrolysis in ring opening, suggested regulation of the cohesin ATPase activity by DNA and Smc3 acetylation, and provided insights into how Pds5 and Wapl (...) open this exit gate. We hypothesize that Pds5, Wapl, and SA1/2 form a rigid scaffold that docks on Scc1 and anchors the N‐terminal domain of Scc1 (Scc1N) to the Smc1 ATPase head. Relative movements between the Smc1‐3 ATPase heads driven by ATP and Wapl disrupt the Smc3‐Scc1 interface. Pds5 binds the dissociated Scc1N and prolongs this open state of cohesin, releasing DNA. We review the evidence supporting this model and suggest experiments that can further test its key principles. (shrink)

Gluten ataxia is a rare immune-mediated neurological disorder caused by the ingestion of gluten. The diagnosis is not straightforward as antibodies are present in only up to 38% of patients, but often at lower titers. The symptoms of ataxia may be mild at the onset but lead to permanent damage if remain untreated. It is characterized by damage to the cerebellum however, the pathophysiology of the disease is not clearly understood. The present study investigated the neurochemical profile of vermis and (...) right cerebellum and structural changes in various brain regions of patients with gluten ataxia and compared it with healthy controls. Volumetric 3-D T1 and T1-weighted magnetic resonance imaging in the three planes of the whole brain and single-voxel 1H- magnetic resonance spectroscopy of the vermis and right cerebellum were acquired on 3 T human MR scanner. The metabolite concentrations were estimated using LC Model while brain volumes were estimated using the online tool volBrain pipeline and CERES and corrected for partial volumes. The levels of neuro-metabolites were found to be significantly lower in vermis, while N-acetyl aspartate + N-acetyl aspartate glutamate and glycerophosphocholine + phosphocholine was lower in cerebellum regions in the patients with gluten ataxia compared to healthy controls. A significant reduction in the white matter of ; reduction in the volumes of cerebellum lobe and thalamus while lateral ventricles were increased in the patients with gluten ataxia compared to healthy controls. The reduced neuronal metabolites along with structural changes in the brain suggested neuronal degeneration in the patients with gluten ataxia. Our preliminary findings may be useful in understanding the gluten-induced cerebral damage and indicated that MRI and MRS may serve as a non-invasive useful tool in the early diagnosis, thereby enabling better management of these patients. (shrink)

Expression of sexually dimorphic behaviors critical for reproduction depends on the organizational actions of steroid hormones on the developing brain. We offer the new hypothesis that transcriptional activities in brain regions executing these sexually dimorphic behaviors are modulated by estrogen‐induced modifications of histone proteins. Specifically, in preoptic nerve cells responsible for facilitating male sexual behavior in rodents, gene expression is fostered by increased histone acetylation and reduced methylation (Me), and, that the opposite set of histone modifications will be found (...) in females. Conversely, in ventromedial hypothalamic neurons that are responsible for coordinating female sexual behavior, transcriptional activities in genetic females are fostered by increased histone acetylation and reduced Me, and, further, that the opposite set of histone modifications will be found in males. Thus, these epigenetic events will guarantee that effects of sex hormone exposure during the neonatal critical period will be translated into lasting sex differences in adult reproductive behaviors. (shrink)

Acetyltransferase enzymes expressed in hepatic and extrahepatic tissues are products of an acetyltransferase gene locus. Acetylation capacity is regulated by simple autosomal Mendelian inheritance of two codominant alleles at this locus. Human slow acetylators are predisposed to bladder cancer from arylamine chemicals. The role of the bladder in arylamine metabolism and of bladder acetyltransferases in the etiology of bladder cancer is not fully understood, but the acetylator genotype‐dependent expression of arylamine N‐acetyltransferase and N‐hydroxyarylamine O‐acetyltransferase in bladder cytosol may contribute (...) towards the genetic predisposition of human slow acetylators to arylamine‐induced bladder cancer. (shrink)

The mammalian pineal gland contains two types of N‐acetyltransferases which act on aromatic amines. One type preferentially acetylates arylamines such as phenetidine and aniline, whereas the other preferentially acetylates arylalkylamines such as tryptamine and phenylethylamine. The two enzymes can be distinguished by (1) molecular size, (2) regulation, and (3) inactivation characteristics. Arylalkylamine N‐acetyltransferase is involved in the regulation of melatonin synthesis in the pineal gland. A specific function of pineal arylamine N‐acetyltransferase has not been established; it may function as a (...) nonspecific detoxification mechanism. (shrink)

Recent magnetic resonance imaging and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1 H magnetic resonance spectroscopy, through measurement of N -acetyl aspartate, a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter, such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis (...) NAWM was studied with MRS, measuring the concentration of N -acetyl derived groups. Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr was significantly lower in NAWM in patients than in controls, as was the absolute concentration of NA. There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group. (shrink)

In this Roots essay, Fritz Lipmann reviews the ways in which a number of activated metabolic intermediates were discovered, and where, not infrequently, he himself played a leading role. The concept of ‘squiggle‐P’ (∼ P) to denote the controversially named ‘high‐energy bond’, the discoveries of acetylphosphate, the activation of carboxylic acids and of amino acids, and of acetyl coenzyme A, are reviewed. In addition, carbamoyl phosphate as perhaps the earliest activated phosphate donor to evolve, and active sulfate, in phosphoadenosine phosphosulfate, (...) are discussed, as well as the remarkable earlier discovery by Buchner and Hahn of how to prepare a yeast extract that fermented carbohydrate to ethanol; this discovery is viewed by Lipmann as the opening chapter in the new sciences of biochemistry and molecular biology. (shrink)

Nucleosomes are the basic elements of chromatin structure. Polyamines, such as spermine and spermidine, are small ubiquitous molecules absolutely required for cell growth. Photoaffinity polyamines bind to specific locations in nucleosomes and can change the helical twist of DNA in nucleosomes. Acetylation of polyamines reduces their affinity for DNA and nucleosomes, thus the helical twist of DNA in nucleosomes could be regulated by cells through acetylation. I suggest that histone and polyamine acetylation act synergistically to modulate chromatin (...) structure. On naked DNA, the photoaffinity spermine bound preferentially to a specific ‘TATA’ sequence element, suggesting that polyamines may be involved in the unusual chromatin structure in this region. Further work is needed to test whether the specificities shown by photoaffinity polyamines are also shown by cellular polyamines; such experiments are now feasible. (shrink)

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can self‐renew indefinitely and contribute to all tissue types of the adult organism. Stem cell‐based therapeutic approaches hold enormous promise for the cure of regenerative diseases. Over the last few years, several studies have attempted to decipher the important role of transcription factor networks and epigenetic regulatory signals in the maintenance of ESC pluripotency, but the exact underlying mechanisms have yet to be identified. Among the epigenetic factors, chromatin dynamics and (...) structure have been found to contribute greatly to maintenance of pluripotency and regulation of differentiation in ESCs. These modifications include: covalent histone acetylation and methylation, histone bivalents and chromatin remodeling, and DNA methylation. Studies in ESCs have shown that genes associated with early development are arranged within a bivalent chromatin structure. This is thought to be a “poised yet repressed” situation, which can be activated upon differentiation. The breakthrough of iPSCs has opened a new era in stem cell biology. During reprogramming, the chromatin state of differentiated cells is reset to an embryonic form via a largely unknown mechanism. In this review, the fundamental impact of chromatin dynamic in ESCs as well as its critical role in the generation of iPSCs is discussed. (shrink)

The Earth agglomerates and heats. Convection cells within the planetary interior expedite the cooling process. Volcanoes evolve steam, carbon dioxide, sulfur dioxide and pyrophosphate. An acidulous Hadean ocean condenses from the carbon dioxide atmosphere. Dusts and stratospheric sulfurous smogs absorb a proportion of the Sun’s rays. The cooled ocean leaks into the stressed crust and also convects. High temperature acid springs, coupled to magmatic plumes and spreading centers, emit iron, manganese, zinc, cobalt and nickel ions to the ocean. Away from (...) the spreading centers cooler alkaline spring waters emanate from the ocean floor. These bear hydrogen, formate, ammonia, hydrosulfide and minor methane thiol. The thermal potential begins to be dissipated but the chemical potential is dammed. The exhaling alkaline solutions are frustrated in their further attempt to mix thoroughly with their oceanic source by the spontaneous precipitation of biomorphic barriers of colloidal iron compounds and other minerals. It is here we surmise that organic molecules are synthesized, filtered, concentrated and adsorbed, while acetate and methane—separate products of the precursor to the reductive acetyl-coenzyme-A pathway—are exhaled as waste. Reactions in mineral compartments produce acetate, amino acids, and the components of nucleosides. Short peptides, condensed from the simple amino acids, sequester ‘ready-made’ iron sulfide clusters to form protoferredoxins, and also bind phosphates. Nucleotides are assembled from amino acids, simple phosphates carbon dioxide and ribose phosphate upon nanocrystalline mineral surfaces. The side chains of particular amino acids register to fitting nucleotide triplet clefts. Keyed in, the amino acids are polymerized, through acid–base catalysis, to alpha chains. Peptides, the tenuous outer-most filaments of the nanocrysts, continually peel away from bound RNA. The polymers are concentrated at cooler regions of the mineral compartments through thermophoresis. RNA is reproduced through a convective polymerase chain reaction operating between 40 and 100°C. The coded peptides produce true ferredoxins, the ubiquitous proteins with the longest evolutionary pedigree. They take over the role of catalyst and electron transfer agent from the iron sulfides. Other iron–nickel sulfide clusters, sequestered now by cysteine residues as CO-dehydrogenase and acetyl-coenzyme-A synthase, promote further chemosynthesis and support the hatchery—the electrochemical reactor—from which they sprang. Reactions and interactions fall into step as further pathways are negotiated. This hydrothermal circuitry offers a continuous supply of material and chemical energy, as well as electricity and proticity at a potential appropriate for the onset of life in the dark, a rapidly emerging kinetic structure born to persist, evolve and generate entropy while the sun shines. (shrink)

Carbon monoxide intoxication leads to acute and chronic neurological deficits, but little is known about the specific noxious mechanisms. 1 H magnetic resonance spectroscopy may allow insight into the pathophysiology of CO poisoning by monitoring neurochemical disturbances, yet only limited information is available to date on the use of this protocol in determining the neurological effects of CO poisoning. To further examine the short-term and long-term effects of CO on the central nervous system, we have studied seven patients with CO (...) poisoning assessed by gray and white matter MRS, magnetic resonance imaging and neuropsychological testing. Five patients suffered from acute high-dose CO intoxication and were in coma for 1–6 days. In these patients, MRI revealed hyperintensities of the white matter and globus pallidus and also showed increased choline and decreased N -acetyl aspartate ratios to creatine, predominantly in the white matter. Lactate peaks were detected in two patients during the early phase of high-dose CO poisoning. Two patients with chronic low-dose CO exposure and without loss of consciousness had normal MRI and MRS scans. On follow-up. five of our seven patients had long-lasting intellectual impairment, including one individual with low-dose CO exposure. The MRS results showed persisting biochemical alterations despite the MRI scan showing normalization of morphological changes. In conclusion, the MRS was normal in patients suffering from chronic low-dose CO exposure; in contrast, patients with high-dose exposure showed abnormal gray and white matter levels of NAA/Cr, Cho/Cr and lactate, as detected by 1 H MRS, suggesting disturbances of neuronal function, membrane metabolism and anaerobic energy metabolism, respectively. Early increases in Cho/Cr and decreases of NAA/Cr may be related to a poor long-term outcome, but confirmation by future studies is needed. (shrink)

Transcriptional repression and silencing have been strongly associated with hypoacetylation of histones. Accordingly, histone deacetylases, which remove acetyl groups from histones, have been shown to participate in mechanisms of transcriptional repression. Therefore, current models of the role of acetylation in transcriptional regulation focus on the acetylation status of histones and designate histone acetyltransferases, which add acetyl groups to histones, as transcriptional coactivators and histone deacetylases as corepressors. In recent years, an accumulation of studies have shown that these enzymes (...) also target non‐histone proteins and that histone deacetylases have clear roles as coactivators at a variety of genes, some of which are key regulators of cell growth and survival. This review summarizes the evidence for histone deacetylases as coactivators and provides models of coactivation mechanisms, some of which integrate roles of acetylated histones and non‐histone proteins in transcription. BioEssays 30:15–24, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

The eukaryotic genome is organized into different domains by cis‐acting elements, such as boundaries/insulators and matrix attachment regions, and is packaged with different degrees of condensation. In the M phase, the chromatin becomes further highly condensed into chromosomes. The first step for transcriptional activation of a given gene, at a particular time during development, in any locus, is the opening of its chromatin domain. This locus needs to be kept in this state in each early G1 phase during every cell (...) cycle. Certain distal enhance elements, including locus control regions (LCRs) and enhancers, are believed to perform this target chromatin domain opening process and several models have been proposed to explain distal enhance action. But they did not explain precisely how a given chromatin domain is opened. Based on various studies, we propose a hypothesis for the mechanism of opening chromatin on a large scale. One important mechanism may involved breaking one or two DNA strands and reducing the linking numbers within chromatin domain. The topological changes can overpass some complexes formed on DNA strands and can be transmitted from specific localized points over a broad region, until boundary elements or insulators are reached. These may initiate downstream events such as propagation of histone acetylation and the binding of transcription factors to proximal promoters and may further augment the action mediated by distal enhancer elements. BioEssays 25:507–514, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Post-translational histone modifications and their biological effects have been described as a ‘histone code’. Independently, Barbieri used the term ‘organic code’ to describe biological codes in addition to the genetic code. He also provided the defining criteria for an organic code, but to date the histone code has not been tested against these criteria. This paper therefore investigates whether the histone code is a bona fide organic code. After introducing the use of the term ‘code’ in biology, the criteria a (...) putative organic code such as the histone code must conform to in order to be recognised as an organic code are described. Our current knowledge of histones and their major post-translational modifications, and the specific protein binding domains that recognise and translate these into specific biological effects, is then reviewed in detail. The histone modification system is then placed in the context of an organic code and it is concluded that it fulfils all the requirements of an organic code. The marks produced on histones by processes such as acetylation and methylation act as organic signs that are translated into unique biological effects, their biological meanings. These translations are accomplished by effector proteins that consist of a binding domain that recognises a specific histone mark and a regulatory domain that mediates the biological effect. Crucially, these domains can be experimentally interchanged between different effector proteins, thus altering the rules that specify the relationships between sign and meaning. The effector proteins therefore fulfil the role of adaptor molecules. (shrink)

During the eukaryotic cell cycle, chromosomes undergo large structural transitions and spatial rearrangements that are associated with the major cell functions of genome replication, transcription and chromosome condensation to metaphase chromosomes. Eukaryotic cells have evolved cell cycle dependent processes that modulate histone:DNA interactions in chromosomes. These are; (i) acetylations of lysines; (ii) phosphorylations of serines and threonines and (iii) ubiquitinations of lysines. All of these reversible modifications are contained in the well‐defined very basic N‐ and C‐ terminal domains of histones. (...) Acetylations and phosphorylations markedly affect the charge densities of these domains whereas ubiquitination adds a bulky globular protein, ubiquitin, to lysines in the C‐terminal tails of H2A and H2B. Histone acetylations are strictly associated with genome replication and transcription; histone H1 and H3 phosphorylations correlate with the process of chromosome condensation. The subunits of histone H1 kinase have now been shown to be cyclins and the p34CDC2 kinase product of the cell cycle control gene CDC2. It is probable that all of the processes that control chromosome structure:function relationships are also involved in the control of the cell cycle. (shrink)

In Escherichia coli, the role of lacA, the third gene of the lactose operon, has remained an enigma. I suggest that its role is the consequence of the need for cells to have safety valves that protect them from the osmotic effect created by their permeases. Safety valves allow them to cope with the buildup of osmotic pressure under accidental transient conditions. Multidrug resistance (MDR) efflux, thus named because of our anthropocentrism, is ubiquitous. Yet, the formation of simple leaks would (...) result in futile influx/efflux cycles. Versatile modification enzymes with low sensitivity solve the problem if the modified metabolite is the one exported by MDR permeases. This may account for the pervasive presence of acetyl-transferases, such as LacA, associated to acetyl-metabolite exporters. This scenario of constraints imposed by efficient influx of metabolites provides us with a model that should be followed when constructing synthetic cells. (shrink)

The N‐terminal domain of histone H4 has been implicated in various nuclear functions, including gene silencing and activation and replication‐linked chromatin assembly. Many of these have been identified by using H4 mutants in the yeast S. cerevisiae. In a recent paper, Megee et al.(1) use this approach to show that mutants in which all four N‐terminal H4 lysines are substituted with glutamines accumulate increased levels of DNA damage. A single lysine, but not an arginine, anywhere in the N‐terminal domain suppresses (...) this phenotype. It is suggested that histone H4 plays a role in maintaining genome integrity through the cell cycle, possibly by a mechanism involving lysine acetylation. (shrink)

Histone post‐translational modifications (PTMs) alter the chromatin architecture, generating “open” and “closed” states, and these structural changes can modulate gene expression under specific cellular conditions. While methylation and acetylation are the best‐characterized histone PTMs, citrullination by the protein arginine deiminases (PADs) represents another important player in this process. In addition to “fine tuning” chromatin structure at specific loci, histone citrullination can also promote rapid global chromatin decondensation during the formation of extracellular traps (ETs) in immune cells. Recent studies now (...) show that PAD4‐mediated citrullination of histone H1 at promoter elements can also promote localized chromatin decondensation in stem cells, thus regulating the pluripotent state. These observations suggest that PAD‐mediated histone deimination profoundly affects chromatin structure, possibly above and beyond that of other PTMs. Additionally, these recent findings further enhance our understanding of PAD biology and the important contributions that these enzymes play in development, health, and disease. (shrink)

The haploid male germ cell differentiation program controls essential steps of male gametogenesis and relies partly on a significant number of sex chromosome‐linked genes. These genes need to escape chromosome‐wide transcriptional repression of sex chromosomes, which occurs during meiosis and is largely maintained in post‐meiotic cells. A newly discovered histone lysine modification, crotonylation (Kcr), marks X/Y‐linked genes that are active in post‐meiotic male germ cells. Histone Kcr, by conferring resistance to transcriptional repressors, could be a dominant element in maintaining these (...) genes active in the globally repressive environment of haploid cell sex chromosomes. Furthermore, the same mark was found associated with post‐meiotically activated genes on autosomes. Histone Kcr therefore appears to be an indicator of the male haploid cell gene expression program and a notable element of genome programming in the post‐meiotic phases of spermatogenesis. (shrink)