Sub-cellular biochemistry最新文献

Healthy brain functioning requires a continuous fine-tuning of gene expression, involving changes in the epigenetic landscape and 3D chromatin organization. Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are three multifactorial neurodegenerative diseases (NDDs) that are partially explained by genetics (gene mutations and genetic risk factors) and influenced by non-genetic factors (i.e., aging, lifestyle, and environmental conditions). Examining comprehensive studies of global and locus-specific (epi)genomic and transcriptomic alterations in human and mouse brain samples at the cell-type resolution has uncovered important phenomena associated with AD. First, DNA methylation and histone marks at promoters contribute to transcriptional dysregulation of genes that are directly implicated in AD pathogenesis (i.e., APP), neuroplasticity and cognition (i.e., PSD95), and microglial activation (i.e., TREM2). Second, the presence of AD genetic risk variants in cell-type-specific distal enhancers (i.e., BIN1 in microglia) alters transcription, presumably by disrupting associated enhancer-promoter interactions and chromatin looping. Third, epigenomic erosion is associated with widespread transcriptional disruption and cell identity loss. And fourth, aging, high cholesterol, air pollution, and pesticides have emerged as potential drivers of AD by inducing locus-specific and global epigenetic modifications that impact key AD-related pathways. Epigenetic studies in ALS/FTD also provide evidence that genetic and non-genetic factors alter gene expression profiles in neurons and astrocytes through aberrant epigenetic mechanisms. We additionally overview the recent development of potential new therapeutic strategies involving (epi)genetic editing and the use of small chromatin-modifying molecules (epidrugs).

Brain disorders, especially neurodegenerative diseases, affect millions of people worldwide. There is no causal treatment available; therefore, there is an unmet clinical need for finding therapeutic options for these diseases. Epigenetic research has resulted in identification of various genomic loci with differential disease-specific epigenetic modifications, mainly DNA methylation. These biomarkers, although not yet translated into clinically approved options, offer therapeutic targets as epigenetic modifications are reversible. Indeed, clinical trials are designed to inhibit epigenetic writers, erasers, or readers using epigenetic drugs to interfere with epigenetic dysregulation in brain disorders. However, since such drugs elicit genome-wide effects and potentially cause toxicity, the recent developments in the field of epigenetic editing are gaining widespread attention. In this review, we provide examples of epigenetic biomarkers and epi-drugs, while describing efforts in the field of epigenetic editing, to eventually make a difference for the currently incurable brain disorders.

Epigenetic mechanisms are key processes that constantly reshape genome activity carrying out physiological responses to environmental stimuli. Such mechanisms regulate gene activity without modifying the DNA sequence, providing real-time adaptation to changing environmental conditions. Both favorable and unfavorable lifestyles have been shown to influence body and brain by means of epigenetics, leaving marks on the genome that can either be rapidly reversed or persist in time and even be transmitted trans-generationally. Among virtuous habits, meditation seemingly represents a valuable way of activating inner resources to cope with adverse experiences. While unhealthy habits, stress, and traumatic early-life events may favor the onset of diseases linked to inflammation, neuroinflammation, and neuroendocrine dysregulation, the practice of mindfulness-based techniques was associated with the alleviation of many of the above symptoms, underlying the importance of lifestyles for health and well-being. Meditation influences brain and body systemwide, eliciting structural/morphological changes as well as modulating the levels of circulating factors and the expression of genes linked to the HPA axis and the immune and neuroimmune systems. The current chapter intends to give an overview of pioneering research showing how meditation can promote health through epigenetics, by reshaping the profiles of the three main epigenetic markers, namely DNA methylation, histone modifications, and non-coding RNAs.

Schizophrenia is a severe and complex psychiatric condition ranking among the top 15 leading causes of disability worldwide. Despite the well-established heritability component, a complex interplay between genetic and environmental risk factors plays a key role in the development of schizophrenia and psychotic disorders in general. This chapter covers all the clinical evidence showing how the analysis of the epigenetic modulation in schizophrenia might be relevant to understand the pathogenesis of schizophrenia as well as potentially useful to develop new pharmacotherapies.

The brain plays a vital role in maintaining homeostasis and effective interaction with the environment, shaped by genetic and environmental factors throughout neurodevelopment and maturity. While genetic components dictate initial neurodevelopment stages, epigenetics-specifically neuroepigenetics-modulates gene expression in response to environmental influences, allowing for brain adaptability and plasticity. This interplay is particularly evident in neuropathologies like Rett syndrome and CDKL5 deficiency syndrome, where disruptions in neuroepigenetic processes underline significant cognitive and motor impairments. The environmental enrichment paradigm, introduced by Donald Hebb in the late 1940s, demonstrates how enriching stimuli-such as complex sensory, social, and cognitive inputs-affect brain structure and function. Despite methodological variability, evidence reveals that enriched environments catalyze beneficial changes in behavior and neuroanatomy, including increased synaptic plasticity, enhanced motor coordination, and improved cognitive performance in rodent models. Additionally, environmental enrichment induces epigenetic modifications that facilitate these outcomes, highlighting the necessity of understanding the mechanisms driving gene expression changes within the context of enriched experiences. Ultimately, this manifold relationship between environment, neuroepigenetic modulation, and brain function highlights the brain's capacity for change, reinforcing the importance of considering environmental factors in studies of neurodevelopment and therapy for neurological disorders.

The human genome consists of 23 chromosome pairs (22 autosomes and one pair of sex chromosomes), with 46 chromosomes in a normal cell. In the interphase nucleus, the 2 m long nuclear DNA is assembled with proteins forming chromatin. The typical mammalian cell nucleus has a diameter between 5 and 15 μm in which the DNA is packaged into an assortment of chromatin assemblies. The human brain has over 3000 cell types, including neurons, glial cells, oligodendrocytes, microglial, and many others. Epigenetic processes are involved in directing the organization and function of the genome of each one of the 3000 brain cell types. We refer to epigenetics as the study of changes in gene function that do not involve changes in DNA sequence. These epigenetic processes include histone modifications, DNA modifications, nuclear RNA, and transcription factors. In the interphase nucleus, the nuclear DNA is organized into different structures that are permissive or a hindrance to gene expression. In this chapter, we will review the epigenetic mechanisms that give rise to cell type-specific gene expression patterns.

In animals, memory formation and recall are essential for their survival and for adaptations to a complex and often dynamically changing environment. During memory formation, experiences prompt the activation of a selected and sparse population of cells (engram cells) that undergo persistent physical and/or chemical changes allowing long-term memory formation, which can last for decades. Over the past few decades, important progress has been made on elucidating signaling mechanisms by which synaptic transmission leads to the induction of activity-dependent gene regulation programs during the different phases of learning (acquisition, consolidation, and recall). But what are the molecular mechanisms that govern the expression of immediate-early genes (IEGs; c-fos, Npas4) and plasticity-related genes (PRGs; Dlg4/PSD95 and Grin2b/NR2B) in memory ensemble? Studies in relatively simple in vitro and in vivo neuronal model systems have demonstrated that synaptic activity during development, or when induced by chemical stimuli (i.e., cLTP, KCl, picrotoxin), activates the NMDAR-Ca²⁺-CREB signaling pathway that upregulates gene expression through changes in the epigenetic landscape (i.e., histone marks and DNA methylation) and/or 3D chromatin organization. The data support a model in which epigenetic modifications in promoters and enhancers facilitate the priming and activation of these regulatory regions, hence leading to the formation of enhancer-promoter interactions (EPIs) through chromatin looping. The exploration of whether similar molecular mechanisms drive gene expression in learning and memory has presented notable challenges due to the distinct phases of learning and the activation of only sparse population of cells (the engram). Consequently, such studies demand precise temporal and spatial control. By combining activity-dependent engram tagging strategies (i.e., TRAP mice) with multi-omics analyses (i.e., RNA-seq, ChiP-seq, ATAC-seq, and Hi-C), it has been recently possible to associate changes in the epigenomic landscape and/or 3D genome architecture with transcriptional waves in engram cells of mice subjected to contextual fear conditioning (CFC), a relevant one-shot Pavlovian learning task. These studies support the role of specific epigenetic mechanisms and of the 3D chromatin organization during the control of gene transcription waves in engram cells. Advancements in our comprehension of the molecular mechanisms driving memory ensemble will undoubtedly play a crucial role in the development of better-targeted strategies to tackle cognitive diseases, including Alzheimer's disease and frontotemporal dementia, among other information-processing disorders.

Catalases are essential enzymes for removal of hydrogen peroxide, enabling aerobic and anaerobic metabolism in an oxygenated atmosphere. Monofunctional heme catalases, catalase-peroxidases, and manganese catalases, evolved independently more than two billion years ago, constituting a classic example of convergent evolution. Herein, the diversity of catalase sequences is analyzed through sequence similarity networks, providing the context for sequence distribution of major catalase families, and showing that many divergent catalase families remain to be experimentally studied.

The global emergence of multidrug resistance (MDR) in gram-negative bacteria has become a matter of worldwide concern. MDR in these pathogens is closely linked to the overexpression of certain efflux pumps, particularly the resistance-nodulation-cell division (RND) efflux pumps. Inhibition of these pumps presents an attractive and promising strategy to combat antibiotic resistance, as the efflux pump inhibitors can effectively restore the potency of existing antibiotics. AcrAB-TolC is one well-studied RND efflux pump, which transports a variety of substrates, therefore providing resistance to a broad spectrum of antibiotics. To develop effective pump inhibitors, a comprehensive understanding of the structural aspect of the AcrAB-TolC efflux pump is imperative. Previous studies on this pump's structure have been limited to individual components or in vitro determination of fully assembled pumps. Recent advancements in cellular cryo-electron tomography (cryo-ET) have provided novel insights into this pump's assembly and functional mechanism within its native cell membrane environment. Here, we present a summary of the structural data regarding the AcrAB-TolC efflux pump, shedding light on its assembly pathway and operational mechanism.

Since the 1970s and for about 40 years, X-ray crystallography has been by far the most powerful approach for determining virus structures at close to atomic resolutions. Information provided by these studies has deeply and extensively enriched and shaped our vision of the virus world. In turn, the ever-increasing complexity and size of the virus structures being investigated have constituted a major driving force for methodological and conceptual developments in X-ray macromolecular crystallography (MX). Landmarks of the structure determination of viral particles, such as the ones from the first animal viruses or from the first membrane-containing viruses, have often been associated with methodological breakthroughs in X-ray crystallography.In recent years, the advent of new detectors with fast frame rate, high sensitivity, and low-noise background has changed the way MX data is collected, enabling new types of studies at X-ray free-electron laser and synchrotron facilities. In parallel, a very high degree of automation has been established at most MX synchrotron beamlines, allowing the screening of large number of crystals with very high throughputs. This has proved crucial for fragment-based drug design projects, of special relevance for the identification of new antiviral drugs.This change in the usage of X-ray crystallography is also mirrored in the recent advances in cryo-electron microscopy (cryo-EM), which can nowadays produce macromolecule structures at resolutions comparable to those obtained by MX. Since this technique is especially amenable for large protein assemblies, cryo-EM has progressively turned into the favored technique to study the structure of large viral particles at high resolution.In this chapter, we present the common ground of proteins and virus crystallography with an emphasis in the peculiarities of virus-related studies.