表观遗传修饰在学习和记忆中的调节作用

学习和记忆行为是大脑的基本功能,它使得生物个体能够更好地适应环境的变化。揭示学习和记忆的分子生物学机制是现代神经生物学发展的目标之一。经过近40年的研究现已初步证实了突触可塑性在学习和记忆中所起的关键作用。而近年来的研究发现,表观遗传修饰对学习和记忆过程具有重要的调控作用。这一发现将有利于进一步揭示学习和记忆的复杂机制,并将为某些认知障碍性疾病的治疗提供新的思路。     

Life in the colonies: learning the alien ways of colonial organisms

Who needs to go to outer space to study alien beings when the oceans of our own planet abound with bizarre and unknown creatures? Many of them belong to sessile clonal and colonial groups, including sponges, hydroids, corals, octocorals, ascidians, bryozoans, and some polychaetes. Their life histories, in many ways unlike our own, are a challenge for biologists. Studying their ecology, behavior, and taxonomy means trying to “think like a colony” to understand the factors important in their lives. Until the 1980s, most marine ecologists ignored these difficult modular organisms. Plant ecologists showed them ways to deal with the two levels of asexually produced modules and genetic individuals, leading to a surge in research on the ecology of clonal and colonial marine invertebrates. Bryozoans make excellent model colonial animals. Their life histories range from ephemeral to perennial. Aspects of their lives such as growth, reproduction, partial mortality due to predation or fouling, and the behavior of both autozooids and polymorphs can be studied at the level of the colony, as well as that of the individual module, in living colonies and over time.     

Epigenetic rules and Darwinian algorithms: The adaptive study of learning and development

Recent efforts toward a Darwinian psychology of human behavior will profit from taking account of prior investigations of proximate phenomena and adaptive mechanisms conducted within the science of biology, and from realizing that adaptive significance and underlying mechanisms must be investigated in concert. Contrary to some recent arguments, evidence of adaptive design is usually manifested initially and most prominently in the behavior (or other “ultimate” phenotypic expressions) of organisms, human or nonhuman, rather than in underlying psychological, physiological, or developmental mechanisms, which are often obscure, and in any case, as adaptive mechanisms, must be investigated secondarily. The reason is that selection acts most directly on behavior, and on its underlying mechanisms only as they influence the behavior. This is as true for learned and cultural behaviors as for any others. Adaptive significance of behavior, and evidence of its underlying design, is thus examined only by studying the behavior itself, its complexity, the situations in which it is expressed, and its effects in different situations. Biological mechanisms of any kind cannot even be identified with confidence, or understood, until, at the least, reasonable inferences have been made about their adaptive functions, what they are, as mechanisms, designed by selection to accomplish. Moreover, what appear to be adaptive psychological, physiological, or other mechanisms, may, as with some expressions of behavior, be incidental effects of still other mechanisms that are adaptive.Adaptation is not restricted to situations in which genes program specifically for particular behavioral alternatives: natural selection of alternative alleles may also yield abilities and tendencies to engage in conditional strategies, to assess costs and benefits in directly or indirectly reproductive terms. In humans, such cost-benefit assessments may be conducted entirely through mental scenario-building, or even through absorbing and judging the mental scenarios of others, without either admission or cognizance of the reproductive significance of the assessment. The goals actually sought may be secondary, tertiary, or even more distantly removed correlates of reproductive success (e.g., status or reputation, which may correlate with power, which may correlate with wealth, which may correlate with access to the resources of reproduction); reproductive success itself may be a concept alien to the actor's conscious motivations, even denied vehemently as a goal. In learned and cultural behaviors, selection has to be not only for the ability to learn but for its patterning, such as for the machinery enabling development of the ability to learn to make appropriate (cultural) decisions.Kin recognition is reviewed as the most prominent example of a set of extensively studied adaptive mechanisms involving learning, and as a central problem with respect to adaptiveness in social behavior. Arguments that the adaptive mechanisms collected under the concept of learning evolve as special, rather than general-purpose devices, raise provocative questions about the evolution of ontogenetic and physiological preparation to deal with environmental novelty, especially in complex social interactions. Evolution of the human psyche, especially its conscious aspects, is briefly discussed as a problem in understanding the history of sociality. It is argued that the principal environment of natural selection leading to the modern human psyche was social, and that on this account the environment of human behavior has not changed as much since the Pleistocene as is often assumed.     

Epigenetic regulation of learning and memory by Drosophila EHMT/G9a

The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the "writers" of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5' and 3' ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease.     

Demonstration of non-neural tryptophan 5-mono-oxygenase in mouse intestinal mucosa.

Tryptophan 5-mono-oxygenase was demonstrated and its activity was measured in mucosal extracts of the mouse digestive tract by means of highly sensitive h.p.l.c. detection. The intestinal enzyme was activated by anaerobic incubation with dithiothreitol, as are the enzymes from mouse mastocytoma cells and bovine pineal gland. The dithiothreitol-enhanced activity was highest at the proximal portion of colon followed by that at the duodenum, where the unenhanced activity/enhanced activity ratio was highest. The enzymic and immunochemical properties of the intestinal tryptophan 5-mono-oxygenase were similar to those of the mastocytoma enzyme. In contrast, the intestinal enzyme was immunochemically different from brain tryptophan 5-mono-oxygenase. The possibility that connective tissue and/or mucosal mast cells are responsible for some of the enzyme activity of the duodenal mucosa was ruled out by the demonstration of the activity in extracts from a mast-cell-deficient mutant mouse (W/Wv). The enzyme in the duodenum was found to reside between the upper villus region and the bottom of the crypt, suggesting that it is mainly of enterochromaffin cell and not of submucosal nerve plexus origin.     

Epigenetic mechanisms in schizophrenia

Epidemiological research suggests that both an individual's genes and the environment underlie the pathophysiology of schizophrenia. Molecular mechanisms mediating the interplay between genes and the environment are likely to have a significant role in the onset of the disorder. Recent work indicates that epigenetic mechanisms, or the chemical markings of the DNA and the surrounding histone proteins, remain labile through the lifespan and can be altered by environmental factors. Thus, epigenetic mechanisms are an attractive molecular hypothesis for environmental contributions to schizophrenia. In this review, we first present an overview of schizophrenia and discuss the role of nature versus nurture in its pathology, where ‘nature’ is considered to be inherited or genetic vulnerability to schizophrenia, and ‘nurture’ is proposed to exert its effects through epigenetic mechanisms. Second, we define DNA methylation and discuss the evidence for its role in schizophrenia. Third, we define posttranslational histone modifications and discuss their place in schizophrenia. This research is likely to lead to the development of epigenetic therapy, which holds the promise of alleviating cognitive deficits associated with schizophrenia.     

Epigenetic marks in melanoma

Melanoma is a highly heterogeneous cancer that comes in different flavors (lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous/mucosal melanoma and other less common subtypes including malignant cellular blue nevus, desmoplastic melanoma, nevoid melanoma, and animal‐type melanoma) and colors (black/bluish or unpigmented). Pathologists have known for many years that melanoma displays notable changes in the nuclear architecture including thick chromatic rims, presence of mitosis, nuclear grooves, and more. It is now evident from other cancers that such changes reflect not only genomic alterations but also non‐genomic changes in both the structure of DNA and the structure of chromatin to which the DNA is bound (nucleosomes). Although aberrant gene expression resulting from DNA methylation has been known for many years, genome alterations resulting from histone modifications became evident in the current decade. In prostate and other cancers, some histone marks have clinical diagnostic and/or prognostic value. Here, we review the current data on epigenetic research in melanoma skin cancers, discuss ways to modify the epigenetic landscape of melanoma for inhibiting its growth, and propose strategies for identifying novel melanoma markers.     

癌症中的表观遗传变化

DNA与组蛋白上的共价标记如何参与癌细胞的产生与扩散,这项研究同时带来了新的治疗策略。     

Epigenetic deregulations in chordoma

Chordoma is a rare type of malignant bone tumour arising from remnant notochord and prognosis of patients with it remains poor as its molecular and genetic mechanisms are not well understood. Increasing evidence has demonstrated that epigenetic mechanisms (DNA methylation, histone modification and nucleosome remodelling), play a crucial role in the pathogenesis of many diseases. Aberrant epigenetic patterns are present in patients with chordoma, indicating a potential role for epigenetic mechanisms inthis malignancy. Furthermore, epigenetic alterations may provide novel biomarkers for diagnosis and prognosis as well as therapeutic targets for treatment. In this review, we discuss relevant epigenetic findings associated with chordoma, and their potential application for diagnosis, prognosis and treatment.     

Epigenetic mechanisms in cognition

Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in postmitotic neurons as a means of consolidating and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an "epigenetic code" in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and we review the therapeutic potential of epigenetic treatments for the amelioration of these conditions.     

Epigenetic heredity in evolution

We discuss the role of cell memory in heredity and evolution. We describe the properties of the epigenetic inheritance systems (EISs) that underlie cell memory and enable environmentally and developmentally induced cell phenotypes to be transmitted in cell lineages, and argue that transgenerational epigenetic inheritance is an important and neglected part of heredity. By looking at the part EISs have played in the evolution of multicellularity, ontogeny, chromosome organization, and the origin of some post-mating isolating mechanisms, we show how considering the role of epigenetic inheritance can sometimes shed light on major evolutionary processes.     

Epigenetic inheritance in evolution

We discuss the role of cell memory in heredity and evolution. We describe the properties of the epigenetic inheritance systems (EISs) that underlie cell memory and enable environmentally and developmentally induced cell phenotypes to be transmitted in cell lineages, and argue that transgenerational epigenetic inheritance is an important and neglected part of heredity. By looking at the part EISs have played in the evolution of multicellularity, ontogeny, chromosome organization, and the origin of some post-mating isolating mechanisms, we show how considering the role of epigenetic inheritance can sometimes shed light on major evolutionary processes.     

The myelin proteolipid protein gene modulates apoptosis in neural and non-neural tissues

Mutations of the myelin proteolipid protein gene (Plp) are associated with excessive programmed cell death (PCD) of oligodendrocytes. We show for the first time that PLP is a molecule ubiquitously expressed in non-neural tissues during normal development, and that the level of native PLP modulates the level of PCD. We analyze three non-neural tissues, and show that native PLP is expressed in trophoblasts, spermatogonia, and cells of interdigital webbing. The non-neural cells that express high levels of native PLP also undergo PCD. The level of PLP expression modulates the level of PCD because mice that overexpress native PLP have increased PCD and mice deficient in PLP have decreased PCD. We show that overexpression of native PLP causes a dramatic acidification of extracellular fluid that, in turn, causes increased PCD. These studies show that the level of native PLP modulates the amount of PCD during normal development via a pH-dependent mechanism.