Assembly of the cricket cercal sensory system: genetic and epigenetic control

The cercal sensory system of the cricket is being examined using anatomical, physiological, and computer simulation techniques in order to better understand the assembly of sensory systems. This particular sensory system is of interest because it functions like numerically more complex vertebrate sensory systems but offers, to the neuroscientist, the technical advantages of a small number of large identified neurons. Two aspects of sensory processing are being examined in this system; the spatial aspects of a stimulus that tell an animal where a target is in its environment, and the qualities of a stimulus that help the animal to identify the stimulus. The spatial aspects of a stimulus are analyzed by a topographic mapping of the animal's sensory environment. The feature extraction machinery for other aspects of the stimulus lacks any obvious anatomical order and is embedded within the topographic map. We are attempting to tease apart the genetic and the epigenetic components of the assembly process for this sensory system. Here we review our progress with emphasis on the epigenetic aspects of its assembly. We describe previously published work on plasticity as well as new experiments focussed on the role of neuronal activity in the assembly of this neural circuit. Finally, we briefly describe simulation experiments that are helping us understand the role of various forms of synaptic plasticity in the determination of receptive fields.     

Epigenetic inheritance, genetic assimilation and speciation.

Epigenetic inheritance systems enable the environmentally induced phenotypes to be transmitted between generations. Jablonka and Lamb (1991, 1995) proposed that these systems have a substantial role during speciation. They argued that divergence of isolated populations may be first triggered by the accumulation of (heritable) phenotypic differences that are later followed and strengthened by genetic changes. The plausibility of this idea is examined in this paper. At first, we discuss the "exploratory" behaviour of an epigenetic inheritance system on a one peak adaptive landscape. If a quantitative trait is far from the optimum, then it is advantageous to induce heritable phenotypic variation. Conversely, if the genotypes get closer to the peak, it is more favorable to canalize the phenotypic expression of the character. This process would lead to genetic assimilation. Next we show that the divergence of heritable epigenetic marks acts to reduce or to eliminate the genetic barrier between two adaptive peaks. Therefore, an epigenetic inheritance system can increase the probability of transition from one adaptive state to another. Peak shift might be initiated by (i) slight changes in the inducing environment or by (ii) genetic drift of the genes controlling epigenetic variability. Remarkably, drift-induced transition is facilitated even if phenotypic variation is not heritable. A corollary of our thesis is that evolution can proceed through suboptimal phenotypic states, without passing through a deep adaptive valley of the genotype. We also consider the consequences of this finding on the dynamics and mode of reproductive isolation.     

Epigenetic Mechanisms of Blood-Pressure Regulation

The role of epigenetic mechanisms involved in blood-pressure regulation has been reviewed. It is known that some periods in early pre- and postnatal ontogenesis are very sensitive to some environmental and endogenous influences. These periods are characterized as highly vulnerable to the formation of a complex of epigenetic changes that may determine the trajectory of the further formation of physiological systems involved in the blood-pressure regulation. Early life influences on these systems may predispose an individual to the development of hypertensive disease in further life. In some cases, the transmission of epigenetic changes to the next generations may resolve the contradiction between the high heritability of arterial hypertensive disease and the low total contribution of polymorphic DNA variants in the population variability of blood pressure values.     

ATR-FTIR redox difference spectroscopy of Yarrowia lipolytica and bovine complex I

ATR-FTIR spectroscopy in combination with electrochemistry has been applied to the redox centers of Yarrowia lipolytica complex I. The redox spectra show broad similarities with previously published data on Escherichia coli complex I and with new data here on bovine complex I. The spectra are dominated by amide I/II protein backbone changes. Comparisons with redox IR spectra of small model ferredoxins demonstrate that these amide I/II changes arise primarily from characteristic structural changes local to the iron-sulfur centers, rather than from global structural alterations as has been suggested previously. Bands arising from the substrate ubiquinone were evident, as was a characteristic 1405 cm(-)(1) band of the reduced form of the FMN cofactor. Other signals are likely to arise from perturbations or protonation changes of a carboxylic amino acid, histidine, and possibly several other specific amino acids. Redox difference spectra of center N2, together with substrate ubiquinone, were isolated from those of the other iron-sulfur centers by selective redox potentiometry. Its redox-linked amide I/II changes were typical of those in other 4Fe-4S iron sulfur proteins. Contrary to published data on bacterial complex I, no center N2 redox-linked protonation changes of carboxylic amino acids or tyrosine were evident, and other residues that could provide its redox-linked protonation site are discussed. Features of the substrate ubiquinone associated with the center N2 spectrum were particularly clear, with firm assignments possible for bands from both oxidized and reduced forms. This is the first report of IR properties of ubiquinone in complex I, and the data could be used to estimate a stoichiometry of 0.2-0.4 per complex I.     

Parametric models of ontogenetic diversities

Modeling of morphogenesis demonstrates that they form rather wide regions of structural stability and narrow zones of instability in parametric space. Within instability zones, small parameter shifts lead to drastic changes in the morphology of buds. These particular zones are the sources of ontogenetic diversities and represent the reserve for evolutionary variation. A topical problem is to construct models based on universal schemes of negative feedbacks between dynamic components of ontogenesis; moreover, the specificity of ontogenesis should be determined by the values of genetic and epigenetic parameters.     

Recent advances in the development of peptide-based inhibitors targeting epigenetic readers of histone lysine acetylation and methylation marks

Inhibitors for epigenetic readers of histone modifications are useful chemical probes to interrogate the functional roles played by their cognate targets in epigenetic regulation and can even serve as drugs for the treatment of diseases associated with the dysregulated targets. However, many epigenetic readers are intractable to small molecules, as the recognition of modified histone peptides commonly involves flat and extended protein surfaces. In contrast, the relatively large sizes and structural complexity of peptides help them achieve tight and specific binding to the target proteins. Increasing efforts have been made to target epigenetic readers using peptide-based inhibitors that can complement small molecules. In this review, we discuss the recent advances in the development of peptide-based inhibitors of lysine acetylation and methylation readers.     

Calcium and myocardial cell injury. An appraisal in the cardiomyopathic hamster

The heart muscle is very compliant within a wide range of physiologic impulses. The adaptive energy of the myocardium depends, however, upon adequate oxygen supply and the functional state of the plasmalemma. These limitations have been well demonstrated in a number of experimental models with emphasis on the essential role of Ca2+ transmembrane movements for maintenance of heart functions and its viability. This postulate appeared quite important when we found that Ca2+ slow channel blockers could prevent necrotic changes in hamster hereditary cardiomyopathy. However, the effectiveness of beta-adrenoagonists when given in low doses seems more difficult to interpret since these agonists can only promote Ca2+ transmembrane movements. We can only surmise that Ca2+ accumulation in cardiomyopathic hearts does not derive from a primary defect of the plasmalemma but rather from an exhausted hypokinetic state that favours Ca2+ accumulation with progressive deterioration of the structural proteins. It is thus inferred that Ca2+ mediates rather than initiates the degradation process which characterizes this inherited cardiomyopathy.     

Current perspectives on the cellular and molecular features of epigenetic ageing

It has been noted for quite some time that DNA methylation levels decline with age. The significance of this change remained unknown until it became possible to measure methylation status of specific sites on the DNA. It was observed that while the methylation of some sites does indeed decrease with age, that of others increase or remain unchanged. The application of machine learning methods to these quantitative changes in multiple sites, allowed the generation of a highly accurate estimator of age, called the epigenetic clock. The application of this clock on large human epidemiological data sets revealed that discordance between the predicted (epigenetic age) and chronological age is associated with many age-related pathologies, particularly when the former is greater than the latter. The epigenetic clock clearly captures to some degree, biological features that accompany the ageing process. Despite the ever-increasing scope of pathologies that are found to be associated with accelerated epigenetic ageing, the basic principles that underlie the ticking of the clock remain elusive. Here, we describe the known molecular and cellular attributes of the clock and consider their properties, and proffer opinions as to how they may be connected and what might be the underlying mechanism. Emerging from these considerations is the inescapable view that epigenetic ageing begins from very early moments after the embryonic stem cell stage and continues un-interrupted through the entire life-course. This appears to be a consequence of processes that are necessary for the development of the organism from conception and to maintain it thereafter through homeostasis. Hence, while the speed of ageing can, and is affected by external factors, the essence of the ageing process itself is an integral part of, and the consequence of the development of life.Impact statementThe field of epigenetic ageing is relatively new, and the speed of its expansion presents a challenge in keeping abreast with new discoveries and their implications. Several reviews have already addressed the great number of pathologies, health conditions, life-style, and external stressors that are associated with changes to the rate of epigenetic ageing. While these associations highlight and affirm the ability of epigenetic clock to capture biologically meaningful changes associated with age, they do not inform us about the underlying mechanisms. In this very early period since the development of the clock, there have been rather limited experimental research that are aimed at uncovering the mechanism. Hence, the perspective that we proffer is derived from available but nevertheless limited lines of evidence that together provide a seemingly coherent narrative that can be tested. This, we believe would be helpful towards uncovering the workings of the epigenetic clock.     

Integrating cybernetic modeling with pathway analysis provides a dynamic, systems-level description of metabolic control

Cybernetic modeling strives to uncover the inbuilt regulatory programs of biological systems and leverage them toward computational prediction of metabolic dynamics. Because of its focus on incorporating the global aims of metabolism, cybernetic modeling provides a systems-oriented approach for describing regulatory inputs and inferring the impact of regulation within biochemical networks. Combining cybernetic control laws with concepts from metabolic pathway analysis has culminated in a systematic strategy for constructing cybernetic models, which was previously lacking. The newly devised framework relies upon the simultaneous application of local controls that maximize the net flux through each elementary flux mode and global controls that modulate the activities of these modes to optimize the overall nutritional state of the cell. The modeling concepts are illustrated using a simple linear pathway and a larger network representing anaerobic E. coli central metabolism. The E. coli model successfully describes the metabolic shift that occurs upon deleting the pta-ackA operon that is responsible for fermentative acetate production. The model also furnishes predictions that are consistent with experimental results obtained from additional knockout strains as well as strains expressing heterologous genes. Because of the stabilizing influence of the included control variables, the resulting cybernetic models are more robust and reliable than their predecessors in simulating the network response to imposed genetic and environmental perturbations.     

Life as physics and chemistry: A system view of biology

Cellular life can be viewed as one of many physical natural systems that extract free energy from their environments in the most efficient way, according to fundamental physical laws, and grow until limited by inherent physical constraints. Thus, it can be inferred that it is the efficiency of this process that natural selection acts upon. The consequent emphasis on metabolism, rather than replication, points to a metabolism-first origin of life with the adoption of DNA template replication as a second stage development. This order of events implies a cellular regulatory system that pre-dates the involvement of DNA and might, therefore, be based on the information acquired as peptides fold into proteins, rather than on genetic regulatory networks. Such an epigenetic cell regulatory model, the independent attractor model, has already been proposed to explain the phenomenon of radiation induced genomic instability. Here it is extended to provide an epigenetic basis for the morphological and functional diversity that evolution has yielded, based on natural selection of the most efficient free energy transduction. Empirical evidence which challenges the current genetic basis of cell and molecular biology and which supports the above proposal is discussed.     

Genetic and epigenetic consequences of recent hybridization and polyploidy in Spartina (Poaceae)

To study the consequences of hybridization and genome duplication on polyploid genome evolution and adaptation, we used independently formed hybrids (Spartina x townsendii and Spartina x neyrautii) that originated from natural crosses between Spartina alterniflora, an American introduced species, and the European native Spartina maritima. The hybrid from England, S. x townsendii, gave rise to the invasive allopolyploid, salt-marsh species, Spartina anglica. Recent studies indicated that allopolyploid speciation may be associated with rapid genetic and epigenetic changes. To assess this in Spartina, we performed AFLP (amplified fragment length polymorphism) and MSAP (methylation sensitive amplification polymorphism) on young hybrids and the allopolyploid. By comparing the subgenomes in the hybrids and the allopolyploid to the parental species, we inferred structural changes that arose repeatedly in the two independently formed hybrids. Surprisingly, 30% of the parental methylation patterns are altered in the hybrids and the allopolyploid. This high level of epigenetic regulation might explain the morphological plasticity of Spartina anglica and its larger ecological amplitude. Hybridization rather than genome doubling seems to have triggered most of the methylation changes observed in Spartina anglica.     

Epigenetic drivers and genetic passengers on the road to cancer

Cancer is traditionally viewed as a primarily genetic disorder, however it is now becoming accepted that cancer is also a consequence of abnormal epigenetic events. Genetic changes and aneuploidy are associated with alterations in DNA sequence, and they are a hallmark of the malignant process. Epigenetic alterations are universally present in human cancer and result in heritable changes in gene expression and chromatin structure over many cell generations without changes in DNA sequence, leading to functional consequences equivalent to those induced by genetic alterations. Importantly, intriguing evidence emerged suggesting that epigenetic changes may precede and provoke genetic changes. In this scenario, epigenetic events are primary events while genetic changes (such as mutations) may simply be a consequence of disrupted epigenetic states. This fact may explain why many genetic screens proved to be limited with regard to cancer causality and pathogenesis. Aberrant epigenetic events affect multiple genes and cellular pathways in a non-random fashion and this can predispose to induction and accumulation of genetic changes in the course of tumour initiation and progression. These considerations are critical for a better understanding of tumourigenesis and molecular events underlying the acquisition of drug resistance, as well as development of novel strategies for cancer therapy and prevention.